[6,6] Fused bicyclic HDAC8 inhibitors

ABSTRACT

The present invention is directed to compounds of Formula I: 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers or thereof, wherein R 1 , R 2 , R 2 ′, L, X, W, Y 1 , Y 2 , Y 3 , and Y 4  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/255,817, filed on Sep. 2, 2016, which claims the benefit of priorityof U.S. Provisional Application No. 62/214,101, filed Sep. 3, 2015, theentire content of each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisinvention is concerned with compounds and compositions inhibiting HDACs,methods of treating diseases associated with HDACs, and methods ofsynthesizing these compounds.

BACKGROUND OF THE INVENTION

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 8 (HDAC8) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-7 and 9-11. (De Ruijteret al., Histone Deacetylases (HDACs): Characterization of the ClassicalHDAC Family. Biochem. J. 370; 737-749 (2003)).

HDAC8 is a zinc-dependent histone deacetylase that is known to recognizea number of histone and non-histone substrates (Wolfson et al., HDAC8Substrates: Histones and Beyond. Biopolymers, 99(2): 112-126 (2013)).For instance, in addition to deacetylating histones H2A/H2B, H3 and H4,HDAC8 can also deacetylate the p52 transcription factor (Wolfson et al.,HDAC8 Substrates: Histones and Beyond. Biopolymers, 99(2): 112-126(2013)). Although HDAC8 contains a nuclear localization sequence, it canalso be found in the cytoplasm of smooth muscle cells (Wolfson et al.,HDAC8 Substrates: Histones and Beyond. Biopolymers, 99(2): 112-126(2013)). Northern analysis suggests that there is very little HDAC8 mRNAwithin the cell at any given time. (De Ruijter et al., HistoneDeacetylases (HDACs): Characterization of the Classical HDAC Family.Biochem. J. 370; 737-749 (2003)).

Diseases in which HDAC8 inhibition may have a potential benefit includecancer, neurologic, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or diorders. (See Benedetti etal., Antiox Redox. Signal. 2014 March; Tang et al., Clin Sci. (Lond).2013 June; 124(11):651-62; West and Johnstone, J. Clin. Invest. 2014January; 124(1):30-9.

Three HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; and belinostat (PXD 101; Beleodaq®) for the treatment ofperipheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus, there isa need for drugs with an improved safety-efficacy profile.

Given HDAC8's role in proliferative diseases, neurological diseases, andinflammatory diseases, there is a need for HDAC8 inhibitors with goodtherapeutic properties.

SUMMARY OF THE INVENTION

One aspect of the invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,isomers, and tautomers thereof,

wherein:

Y₁, Y₂, Y₃, and Y₄ are each independently N, C, or CR₃, provided thatwhen bonded to —C(O)NHOH any of Y₁, Y₂, Y₃, or Y₄ is C;

X is selected from the group consisting of S(O)₂, S(O), S, O, C(═O), andC(R₄)(R₅);

W is C(R₄)(R₅) or O;

R₁ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl, aryl, heteroaryl, 3- to8-membered heterocycle, —(CH₂)_(n)—R^(a), —(CH₂)_(n)—O—(CH₂)_(p)—R^(a),—S(O)₂R^(a), —C(O) R^(a), or —C(O)N(R^(a))(R^(b)), wherein each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, orheterocycle is optionally substituted with one or more —OH, halogen,oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, heterocycle, aryl,heteroaryl, or R₄;

R^(a) is at each occurrence, hydrogen, halogen, OH, NH₂, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₄-C₈cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or—C(O)N(R₁₀)(R₁₁), wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substitutedwith one or more —OH, R_(4′), R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂,—OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆),—C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl;

R^(b) is at each occurrence, hydrogen, halogen, OH, NH₂, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₄-C₈cycloalkenyl, aryl, heteroaryl, 3- to 8-membered heterocycle, or—C(O)N(R₁₀)(R₁₁), wherein each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, or heterocycle is optionally substitutedwith one or more —OH, R_(4′), R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂,—OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆),—C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl;

or R^(a) and R^(b) can combine with the carbon or nitrogen to which theyare attached to form a C₃-C₈ cycloalkyl, or 3- to 8-membered heterocycleoptionally substituted with one or more substituent selected from R_(4′)and R_(5′), wherein R_(4′) and R_(5′) independently at each occurrenceare H or —C₁-C₆ alkyl; R₂ and R₂′ are each independently hydrogen, C₁-C₆alkyl, C₁-C₆ alkoxy, —OH, halogen, —NO₂, —NH₂, —CN, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl, aryl, heteroaryl, 3- to8-membered heterocycle, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle is optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy; or

R₂ and R₂′ can combine with the carbon to which they are attached toform an oxo group, C₃-C₈ cycloalkyl, or 3- to 8-membered heterocycle;

R₃ is independently, in each occurrence, hydrogen, halogen, OH, CN, NO₂,NH₂, C₁-C₃ alkyl, or C₁-C₃ alkoxy;

each R₄ or R₅ is each independently, at each occurrence, hydrogen,halogen, OH, NH₂, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₄-C₈ cycloalkenyl, aryl, heteroaryl, 3- to8-membered heterocycle, or —C(O)N(R₁₀)(R₁₁), wherein each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, orheterocycle is optionally substituted with one or more —OH, R_(4′),R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁- C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl;

or R₄ and R₅ can combine with the carbon or nitrogen to which they areattached to form an oxo group, C₃-C₈ cycloalkyl, or 3- to 8-memberedheterocycle optionally substituted with one or more substituent selectedfrom R₄ and R_(5′), wherein R_(4′) and R_(5′) independently at eachoccurrence are H or —C₁-C₆ alkyl;

or R_(4′) and R_(5′) together when attached to the same atom form aC₃-C₈ spirocycloalkyl ring; or R_(4′) and R_(5′) together when attachedto the same atom form a C₃-C₈ spiroheterocycloalkyl ring; or R_(4′) andR_(5′) together when attached to adjacent atoms form an aryl ring, aheteroaryl ring, a C₃-C₈ cycloalkyl, or a 3- to 8-membered heterocycle,wherein the spirocycloalkyl, spiroheterocycloalkyl, heteroaryl,cycloalkyl or heterocycle is optionally substituted with one or moregroups selected from OH, halogen, —C₁-C₆ alkyl or C(O)OR₆;

R₆ and R₇ are each independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, aryl, heteroaryl, heterocycle, —S(O)₂NR₈R₉, —S(O)₂R₈,—C(O)R₈, —CO₂R₈, —S(O)R₈, or —S(O)NR₈R₉, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocycle isoptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, heterocycle, aryl, heteroaryl or

R₆ and R₇ together with the atom to which they are attached form a C₃-C₈cycloalkyl or a 3- to 8-membered heterocycle, wherein the cycloalkyl orthe heterocycle is optionally substituted with one or more groupsselected from halogen, oxo and C₁-C₆ alkyl;

R₈ and R₉ are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, heteroaryl, or 3- to8-membered heterocycle, wherein each is optionally substituted with oneor more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle,aryl, or heteroaryl;

R₁₀ and R₁₁ are each independently hydrogen, C₁-C₆ alkyl, aryl, C₁-C₆alkylaryl or 3- to 8-membered heterocycle, wherein aryl, arylalkyl andheterocycle are optionally substituted with one or more groups selectedfrom halogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy; or

R₁₀ and R₁₁ can combine to form a 3- to 8-membered heterocycleoptionally substituted with one or more R₁₂;

R₁₂ is H or C₁-C₆ alkyl or two adjacent R₁₂ can combine to form an arylor heteroaryl group;

n is an integer from 1 to 6; and

p is an integer from 0 to 2;

provided that the compound is notN-hydroxy-1-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxamide.

Another aspect of the invention relates to a method of treating adisease or disorder associated with HDAC8 modulation in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound of Formula I.

Another aspect of the invention is directed to a method of inhibiting ahistone deacetylase, for instance a zinc-dependent histone deacetylasesuch as HDAC8. The method involves administering to a patient in needthereof an effective amount of a compound of Formula I.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant. The pharmaceuticalcomposition can be effective for treating a disease or disorderassociated with HDAC8 modulation in a subject in need thereof. Thepharmaceutical compositions can comprise the compounds of the presentinvention for use in treating diseases described herein. Thecompositions can contain at least one compound of the invention and apharmaceutically acceptable carrier. The invention also provides the useof the compounds described herein in the manufacture of a medicament forthe treatment of a disease associated with HDACs.

The present invention also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present invention also provides compounds that are useful ininhibiting zinc-dependent HDAC enzymes, and in particular HDAC8. Thesecompounds can also be useful in the treatment of diseases includingcancer.

The present invention further provides compounds that can inhibit HDAC8.In some embodiments, the efficacy-safety profile of the compounds of thecurrent invention can be improved relative to other known HDAC8inhibitors. Additionally, the present technology also has the advantageof being able to be used for a number of different types of diseases,including cancer and non-cancer indications. Additional features andadvantages of the present technology will be apparent to one of skill inthe art upon reading the Detailed Description of the Invention, below.

DETAILED DESCRIPTION OF THE INVENTION

HDAC8 is a zinc-dependent histone deacetylase that is known to recognizea number of non-histone substrates (Wolfson et al., HDAC8 Substrates:Histones and Beyond. Biopolymers, 99(2): 112-126 (2013), hereinincorporated by reference in its entirety). It contains a nuclearlocalization sequence and is thus commonly localized within the cellnucleus. The present invention provides inhibitors of HDAC8 and methodsfor using the same to treat disease.

In a first aspect of the invention, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R₁, R₂, R₂′, L, X, W, Y¹, Y²,Y³, and Y⁴ are described as above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆ alkyl, —C₁-C₆alkyl, —O—C₂-C₆alkenyl, —O—C₂-C₆ alkynyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl,—OC(O)OC₁-C₆ alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,—S(O)₂—C₁-C₆ alkyl, —S(O)NHC₁-C₆ alkyl, and —S(O)N(C₁-C₆ alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

The term “heteroaryl” means a monovalent monocyclic or bicyclic aromaticradical of 5 to 12 ring atoms or a polycyclic aromatic radical,containing one or more ring heteroatoms selected from N, O, or S, theremaining ring atoms being C. Heteroaryl as herein defined also means abicyclic heteroaromatic group wherein the heteroatom(s) is selected fromN, O, or S. The aromatic radical is optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl,pyrimidinyl, imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,benzopyranyl, thiazolyl, and derivatives thereof. Furthermore whencontaining two fused rings the heteroaryl groups herein defined may havean unsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these heteroaryl groups includeindolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran,chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆ alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyland neopentyl.

“Alkylenyl” as herein defined refers to groups of general formula—(CH₂)_(n)— where n is an integer from 1 to 6. Suitable examples ofalkylenyl groups include methylenyl, ethylenyl, and propylenyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 3-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₃-C₈ cycloalkenyl is acycloalkenyl group containing between 3 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized nt electrons (aromaticity) shared among the ring carbonor heteroatoms. Heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heteroycyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

“Aralkyl” or “arylalkyl” refers to an a C₁-C₆ alkyl group, as definedherein above, substituted with an aryl ring containing from 3 to 24 ringatoms per ring. For example, arylalkyl groups herein described can havethe following formula

where n is an integer from 1 to 6. Non-limiting examples of suitablearalkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. Thebond to the parent moiety is through the alkyl.

The term “cycloalkylalkyl refers to a monocyclic saturated carbon ringscontaining 3-18 carbon atoms further substituted with C₁-C₆ alkylgroups. In general cycloalkylalkyl groups herein described display thefollowing formula

where m is an integer from 1 to 6 and n is an integer from 1 to 16.

As used herein, the term “halo” or “halogen” means fluoro, chloro,bromo, or iodo.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₃-C₁₂spirocycle is a spirocycle containing between 3 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the invention.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug”, as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(i.e., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In one embodiment of the compounds of Formula I, X is —O—.

In one embodiment of the compounds of Formula I, X is —SO₂—.

In one embodiment of the compounds of Formula I, X is —CR₄R₅—.

In one embodiment of the compounds of Formula I, Y₁, Y₂ and Y₄ are all—CR₂—.

In one embodiment of the compounds of Formula I, Y₁, Y₂ and Y₄ are all—CR₃—.

In one embodiment of the compounds of Formula I, Y₂, Y₃ and Y₄ are all—CR₃—.

In one embodiment of the compounds of Formula I, Y₂, Y₂ and Y₄ are all—CR₃—.

In one embodiment of the compounds of Formula I, one of Y₁, Y₂, Y₃, orY₄ is N.

In one embodiment, R₁ is —(CH₂)_(n)—R^(a). In another embodiment R^(a)is optionally substituted aryl. In a further embodiment n is 1.

In one embodiment, R₂ and R₂′ can combine with the carbon to form anoxo.

In another embodiment, R₄ is H and R₅ is —C(O)N(R₁₀)(R₁).

In one embodiment, W is CH₂. In another embodiment, W is O.

In one embodiment of the compounds of Formula I, the compound is of theFormula IA:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers and stereoisomers thereof.

In some embodiments of the compounds of IA, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-1a:

In some embodiments of the compounds of IA-1a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-1b:

In some embodiments of the compounds of IA-1b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-1c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3a:

In some embodiments of the compounds of IA-1d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2a:

In some embodiments of the compounds of IA-2a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2b:

In some embodiments of the compounds of IA-2b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2d:

In some embodiments of the compounds of IA-2d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3a:

In some embodiments of the compounds of IA-3a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3b:

In some embodiments of the compounds of IA-3b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3d:

In some embodiments of the compounds of IA-3d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-4a:

In some embodiments of the compounds of IA-4a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-4b:

In some embodiments of the compounds of IA-4b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-4c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-4d:

In some embodiments of the compounds of IA-4d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theFormula IB:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers and stereoisomers thereof.

In one embodiment of the compounds of Formula I, the compound is of theformula IB-1a:

In some embodiments of the compounds of IB-1a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-1b:

In some embodiments of the compounds of IB-1b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-1c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-3a:

In some embodiments of the compounds of IB-1d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-1e:

In some embodiments of the compounds of IA-1e, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2a:

In some embodiments of the compounds of IB-2a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-2b:

In some embodiments of the compounds of IB-2b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-2c:

In one embodiment of the compounds of Formula I, the compound is of theformula IA-2d:

In some embodiments of the compounds of IB-2d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-3a:

In some embodiments of the compounds of IB-3a, R₁ is —(CH₂)_(n)—R^(a)

In one embodiment of the compounds of Formula I, the compound is of theformula IB-3b:

In one embodiment of the compounds of Formula I, the compound is of theformula IB-3c:

In some embodiments of the compounds of IB-3c, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-3d:

In some embodiments of the compounds of IB-3d, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-4a:

In some embodiments of the compounds of IB-4a, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-4b:

In some embodiments of the compounds of IB-4b, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-4c:

In some embodiments of the compounds of IB-4c, R₁ is —(CH₂)_(n)—R^(a).

In one embodiment of the compounds of Formula I, the compound is of theformula IB-4d:

In some embodiments of the compounds of IB-4d, R₁ is —(CH₂)_(n)—R^(a).

In some of the forgoing embodiments of the Formulae IA and IB, n is 1and R^(a) is optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted 3- to 8-membered heterocycle.

In some of the forgoing embodiments of the Formulae IA and IB, n is 1and R^(a) is aryl optionally substituted with one or more —OH, R_(4′),R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl.

In some of the forgoing embodiments of the Formulae IA and IB, n is 1and R^(a) is heteroaryl optionally substituted with one or more —OH,R_(4′), R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇),C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl.

In some of the forgoing embodiments of the Formulae IA and IB, n is 1and R^(a) is 3- to 8-membered heterocycle optionally substituted withone or more —OH, R_(4′), R_(5′), halogen, oxo, (CH₂)_(n)OR₆, —NO₂, —OR₆,—N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl.

In an illustrative embodiment, the compound of Formula I is:

-   N6-hydroxy-4-methyl-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-1);-   4-benzyl-N6-hydroxy-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-2);-   N-hydroxy-4-methyl-2-(spiro[cyclopropane-1,3′-indoline]-1′-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-3);-   4-benzyl-N-hydroxy-2-(spiro[cyclopropane-1,3′-indoline]-1′-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-4);-   N2-benzyl-N6-hydroxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-5);-   N2,4-dibenzyl-N6-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-6);-   N7-hydroxy-4-methyl-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide    (I-7);-   4-benzyl-N7-hydroxy-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide    (I-8);-   N-hydroxy-4-methyl-2-(spiro[cyclopropane-1,3′-indoline]-1′-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-9);-   4-benzyl-N-hydroxy-2-(spiro[cyclopropane-1,3′-indoline]-1′-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-10);-   N2-benzyl-N7-hydroxy-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide    (I-11);-   N2,4-dibenzyl-N7-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide    (I-12);-   N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxamide    (I-13);-   1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-5-carboxamide    (I-14);-   N-hydroxy-4-(3-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide    (I-15);-   N-hydroxy-4-(1-(4-(methylsulfonyl)phenyl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide    (I-16);-   N-hydroxy-3-oxo-4-(4-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamide    (I-17);-   N-hydroxy-3-oxo-4-(3-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-18);-   N-hydroxy-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-19);-   4-((2-cyclopropylthiazol-4-yl)methyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-20);-   N-hydroxy-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-21);-   N-hydroxy-4-(2-methylallyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-22);-   4-(2,6-dichlorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-23);-   4-(3-fluorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-24);-   N-hydroxy-4-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-25);-   N-hydroxy-4-(2-morpholino-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-26);-   4-(2-fluorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-27);-   N-hydroxy-4-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-28);-   N-hydroxy-4-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-29);-   4-((1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-30);-   4-(cyclobutylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-31);-   4-benzyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-32);-   4-(3-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-33);-   4-(4-chlorophenethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-34);-   N-hydroxy-3-oxo-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-35);-   N-hydroxy-3-oxo-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-36);-   4-(4-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-37);-   N-hydroxy-4-(4-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-38);-   N-hydroxy-3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-39);-   N-hydroxy-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-40);-   4-allyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-41);-   4-cyclopentyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-42);-   N-hydroxy-4-(2-methoxyethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-43);-   N-hydroxy-4-(4-methylpent-3-en-1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-44);-   4-butyl-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-45);-   4-(sec-butyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-46);-   N-hydroxy-4-((1-methylpiperidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-47);-   N-hydroxy-3-oxo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-48);-   4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-49);-   4-(2-(cyclopropylmethoxy)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-50);-   4-(2-(cyclopropyl(methyl)amino)-2-oxoethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-51);-   4-(2-(1,1-dioxidoisothiazolidin-2-yl)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-52);-   N-hydroxy-3-oxo-4-(2-(2,2,2-trifluoroethoxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-53);-   4-(2-(1,1-dioxidotetrahydrothiophen-3-yl)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-54);-   N-hydroxy-3-oxo-4-(2-(4-(trifluoromethyl)phenoxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-55);-   4-(2-(4-(N,N-dimethyl    sulfamoyl)phenoxy)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-56);-   N-hydroxy-4-isobutyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-57);-   N-hydroxy-3-oxo-4-phenethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-58);-   N-hydroxy-4-isopentyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-59);-   N-hydroxy-4-(3-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-60);-   N-hydroxy-3-oxo-4-(pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-61);-   4-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-62);-   N-hydroxy-4-(2-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-63);-   4-(4-chlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-64);-   N-hydroxy-3-oxo-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-65);-   N-hydroxy-3-oxo-4-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-66);-   N-hydroxy-3-oxo-4-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-67);-   N-hydroxy-4-(3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-68);-   4-(2-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-69)-   4-(4-(tert-butyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-70);-   4-(3,4-difluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-71);-   N-hydroxy-4-(2-methyl-5-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-72);-   4-(2-fluoro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-73);-   4-(2-fluoro-3-methylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-74);-   4-([1,1′-biphenyl]-3-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-75);-   N-hydroxy-4-((4-methyl-2-phenylthiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-76);-   N-hydroxy-3-oxo-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-77);-   N-hydroxy-4-pentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-78);-   N-hydroxy-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-   1,1-dioxide (I-79);-   N-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide-1,1-dioxide    (I-80);-   N-hydroxy-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide    (I-81);-   N-hydroxy-4-(4-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide    (I-82);-   4-benzyl-N-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-83);-   N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-84);-   N-hydroxy-2-methyl-4-(4-(methyl    sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-85);-   N-hydroxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-86);-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-87);-   4-(4-((difluoromethyl)sulfonyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-88);-   N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-89);-   N-hydroxy-4-(4-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-90);-   N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-91);-   N-hydroxy-2-methyl-4-(4-(methyl    sulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-92);-   4-(2-chloro-4-(methylsulfonyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-93);-   N-hydroxy-4-(1-(4-(methyl    sulfonyl)phenyl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-94);-   4-(1-(2-fluorophenyl)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-95);-   4-(1-(2,6-difluorophenyl)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-96);-   N-hydroxy-4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-97);-   N-hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-98);-   2-ethyl-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-99);-   N-hydroxy-2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-100);-   N-hydroxy-4-(4-methoxybenzyl)-3-oxo-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-101);-   2-benzyl-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-102);-   2-(tert-butyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-103);-   2-(2-aminoethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-104);-   2-(2-(dimethylamino)ethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-105);-   1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-7-carboxamide    (I-106);-   1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-6-carboxamide    (I-107);-   4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-108);-   4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide    (I-109);-   N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxamide    (I-110);-   N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide    (I-111);-   N-hydroxy-1-(4-methoxybenzoyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide    (I-112);-   N-hydroxy-4-(4-methoxybenzoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-113);-   4-(cyclohexanecarbonyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-114);-   N-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-115);-   4-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-116);-   N-hydroxy-4-(4-methylbenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-117);-   4-(4-chlorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-118);-   N-hydroxy-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-119);-   N-hydroxy-4-(4-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-120);-   N-hydroxy-4-(3-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-121);-   N-hydroxy-4-(3-methylbenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-122);-   4-(3-chlorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-123);-   N-hydroxy-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-124);-   N-hydroxy-4-(3-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-125);-   N-hydroxy-4-(2-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-126);-   N-hydroxy-4-(2-methylbenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-127);-   4-(2-chlorobenzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-128);-   N-hydroxy-4-(2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-129);-   N-hydroxy-4-(2-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-130);-   4-(2-(difluoromethoxy)benzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-131);-   4-(3-(difluoromethoxy)benzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-132);-   4-(cyclohexylmethyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-133);-   4-(2-chloro-4-(methylsulfonyl)benzyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-134);-   N-hydroxy-4-(1-(4-(methylsulfonyl)phenyl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-135);-   4-(1-(2-chlorophenyl)ethyl)-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-136);-   N-hydroxy-4-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-137);-   N-hydroxy-4-(3-methoxy-4-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-138);-   N-hydroxy-4-(4-methoxy-3-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-139);-   4-benzoyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-140);-   N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-141);-   N-hydroxy-4-(4-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-142);-   4-(3-chlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-143);-   N-hydroxy-3-oxo-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-144);-   N-hydroxy-4-(3-(methylsulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-145);-   N-hydroxy-3-oxo-4-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-146);-   4-(2-chlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-147);-   N-hydroxy-4-(2-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-148);-   4-(cyclohexylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-149);-   N-hydroxy-3-oxo-4-(4-(piperidine-1-carbonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-150);-   N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-151);-   N-hydroxy-2-methyl-4-(4-(methyl    sulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-152);-   4-benzyl-N-hydroxy-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-153);-   4-benzyl-N-hydroxy-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-154);-   N-hydroxy-4-(4-methoxybenzyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-155);-   N-hydroxy-4-(2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-156);-   N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1′-cyclobutane]-6-carboxamide    (I-157);-   N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1′-cyclohexane]-6-carboxamide    (I-158);-   4-(2-chloro-4-methoxybenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-159);-   4-(2-fluoro-4-methoxybenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-160);-   4-(4-chloro-2-fluorobenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-161);-   (R)-N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-162);-   8-fluoro-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-163);-   4-(4-(1H-pyrazol-1-yl)benzyl)-8-fluoro-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-164);-   N-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxamide    (I-165);-   1-(4-(1H-pyrazol-1-yl)benzyl)-N-hydroxy-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxamide    (I-166);-   N-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-167);-   4-(4-(1H-pyrazol-1-yl)benzyl)-N-hydroxy-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-168);-   N6-hydroxy-4-(4-methoxybenzyl)-N2,N2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-169);-   N⁶-hydroxy-4-(4-methoxybenzyl)-N²-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-170);-   N-hydroxy-4-(4-methoxybenzyl)-2-(morpholine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-171);-   N6-hydroxy-4-(4-methoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide    (I-172);-   4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-173);-   tert-butyl    2-((6-(hydroxycarbamoyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate    (I-174);-   4-(4-(1H-1,2,4-triazol-1-yl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-175);-   N-hydroxy-3-oxo-4-(4-(pyrrolidin-1-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-176);-   N-hydroxy-4-(4-morpholinobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-177);-   N-hydroxy-3-oxo-4-((2-phenyloxazol-5-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-178);-   N-hydroxy-3-oxo-4-((2-phenyloxazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-179);-   N-hydroxy-3-oxo-4-((2-phenyl-2H-1,2,3-triazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-180);-   tert-butyl    6-((6-(hydroxycarbamoyl)-3-oxo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate    (I-181);-   N-hydroxy-4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-182);-   N-hydroxy-4-((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-183);-   (+/−)-4-(chroman-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-184);-   (+/−)-4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-185);-   4-(4-acetamidobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-186);-   4-(4-(1H-imidazol-1-yl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-187);-   N-hydroxy-3-oxo-4-(4-(2-oxopyrrolidin-1-yl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-188);-   4-(4-(N,N-dimethylsulfamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-189);-   N-hydroxy-4-(4-(morpholine-4-carbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-190);-   N-hydroxy-3-oxo-4-((5-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-191);-   N-hydroxy-3-oxo-4-(4-(pyrrolidine-1-carbonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-192);-   N-hydroxy-3-oxo-4-((1-phenyl-1H-1,2,4-triazol-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-193);-   4-(2,4-dimethoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-194);-   4-(2-(4-fluorophenylamino)-2-oxoethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-195);-   N-hydroxy-4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-196);-   N-hydroxy-4-(3-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-197);-   N-hydroxy-3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-198);-   N-hydroxy-4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-199);-   4-((1H-indol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-200);-   4-((1-cyanoindolizin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-201);-   N-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-202);-   4-((1H-indazol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-203);-   N-hydroxy-3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide    (I-204);-   N-hydroxy-3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-205);-   4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-206);-   N-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-207);-   N-hydroxy-4-((6-methoxythiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-208);-   4-((6-chlorothiazolo[5,4-b]pyridin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-209);-   N-hydroxy-4-((5-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-210);-   N-hydroxy-4-((5-methoxythiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-211);-   N-hydroxy-3-oxo-4-((5-(trifluoromethyl)thiazolo[5,4-b]pyridin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-212);-   N-hydroxy-4-((6-methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-213);-   N-hydroxy-3-oxo-4-(pyridin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-214);-   N-hydroxy-3-oxo-4-(pyridin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-215);-   N-hydroxy-4-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-216);-   4-((5-fluorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-217);-   4-((6-fluorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-218);-   4-(3,4-dimethylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-219);-   N-hydroxy-3-oxo-4-(3-phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-220);-   N-hydroxy-4-(4-(oxazol-2-yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-221);-   N-hydroxy-3-oxo-4-((1-phenyl-1H-pyrazol-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-222);-   N-hydroxy-3-oxo-4-((1-phenyl-1H-pyrazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-223);-   4-(4-(1H-pyrazol-1-yl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-224);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(3-phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-225);-   4-(3-(4-chlorophenoxy)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-226);-   4-(3-(4-chlorophenoxy)benzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-227);-   N-hydroxy-3-oxo-4-(2-phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-228);-   N-hydroxy-3-oxo-4-(4-phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-229);-   N-hydroxy-4-(naphthalen-1-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-230);-   N-hydroxy-3-oxo-4-(quinolin-6-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-231);-   N-hydroxy-3-oxo-4-(quinolin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-232);-   N-hydroxy-3-oxo-4-((6-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-233);-   N-hydroxy-3-oxo-4-((5-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-234);-   4-(2-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-235);-   4-(3-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-236);-   4-(4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-237);-   N-hydroxy-4-((2-methyl-2H-indazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-238);-   N-hydroxy-4-((2-methylbenzo[d]oxazol-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-239);-   N-hydroxy-4-((2-methyl-2H-indazol-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-240);-   N-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide    (I-241);-   4-(2-chloro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-242);-   4-(3-chloro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-243);-   N-hydroxy-4-(4-methoxy-3-methylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-244);-   4-(3-fluoro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-245);-   N-hydroxy-4-(4-methoxy-3-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-246);-   4-(2,3-difluoro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-247);-   4-(2,6-difluoro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-248);-   N-hydroxy-4-(4-methoxy-2-(trifluoromethyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-249);-   4-(4-ethoxy-3,5-difluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-250);-   4-([1,1′-biphenyl]-4-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-251);-   4-(2,5-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-252);-   4-(2,6-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-253);-   4-(2,3-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-254);-   4-((5-chloro-2-phenylthiazol-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-255);-   4-(2,4-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-256);-   4-([1,1′-biphenyl]-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-257);-   4-(3,4-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-258);-   4-(2-chloro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-259);-   4-((6-chloro-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-260);-   4-((5-chloro-6-methylbenzo[d]oxazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-261);-   N-hydroxy-3-oxo-4-(2-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-262);-   N-hydroxy-3-oxo-4-(3-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-263);-   N-hydroxy-3-oxo-4-(4-((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-264);-   4-(2-fluoro-3-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-265);-   4-(3-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-266);-   4-(4-fluoro-3-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-267);-   4-(5-fluoro-2-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-268);-   4-((6-chloro-1-ethyl-1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-269);-   4-(2-chloro-4-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-270);-   N-hydroxy-3-oxo-4-((2-phenylthiazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-271);-   4-((5-chlorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-272);-   4-(2-chloro-6-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-273);-   4-(2-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-274);-   4-(2-fluoro-6-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-275);-   4-(3-fluoro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-276);-   4-(4-fluoro-2-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-277);-   4-((6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-278);-   4-((1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-279);-   4-(2,4-dimethylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-280);-   N-hydroxy-4-((1-isopropyl-1H-benzo[d]imidazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-281);-   N-hydroxy-3-oxo-4-((1-propyl-1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-282);-   N-hydroxy-4-((2-methyl-4-propylthiazol-5-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-283);-   4-((3-benzyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-284);-   N-hydroxy-4-((5-methoxybenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-285);-   N-hydroxy-4-((5-methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-286);-   4-((6-chlorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-287);-   4-(benzo[d]oxazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-288);-   4-(benzo[d]thiazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-289);-   4-((5-chlorobenzo[d]thiazol-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-290);-   4-((6-fluorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-291);-   N-hydroxy-2,2-dimethyl-4-((6-methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-292);-   N-hydroxy-4-(imidazo[1,2-a]pyridin-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-293);-   4-((6-chlorobenzo[d]oxazol-2-yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-294);-   4-(benzo[d]thiazol-2-ylmethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-295);-   4-((5-chlorobenzo[d]thiazol-2-yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-296);-   N-hydroxy-2,2-dimethyl-3-oxo-4-phenethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-297);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(3-phenylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-298);-   4-(2,6-dichlorobenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-299);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(3-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-300);-   4-(4-chlorophenethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-301);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(2-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-302);-   (S)—N-hydroxy-2,2-dimethyl-3-oxo-4-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-303);-   4-(cyclohexylmethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-304);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-305);-   4-([1,1′-biphenyl]-4-ylmethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-306);-   N-hydroxy-2,2-dimethyl-3-oxo-4-((2-phenylthiazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-307);-   4-((5-chloro-2-phenylthiazol-4-yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-308);-   4-((5-benzyl-2-phenylthiazol-4-yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-309);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-310);-   4-([1,1′-biphenyl]-3-ylmethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-311);-   4-(3,4-dichlorobenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-312);-   4-(4-(tert-butyl)benzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-313);-   4-(4-(benzyloxy)benzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-314);-   4-([1,1′-biphenyl]-2-ylmethyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-315);-   4-(3,4-dimethylbenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-316);-   N-hydroxy-2,2-dimethyl-4-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-317);-   4-cinnamyl-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-318);-   N-hydroxy-2,2-dimethyl-3-oxo-4-(3-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-319);-   N-hydroxy-2,2-dimethyl-3-oxo-4-((5-phenylisoxazol-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-320);-   4-(2-fluoro-4-(trifluoromethyl)benzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-321);-   4-(2-fluoro-4-(trifluoromethoxy)benzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-322);-   N-hydroxy-4-(naphthalen-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamide    (I-323);-   4-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-324);-   4-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-325);-   N-hydroxy-3-oxo-4-((2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-326);-   N-hydroxy-4-((6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-327);-   N-hydroxy-3-oxo-4-((7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-328);-   N-hydroxy-3-oxo-4-((7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-329);-   N-hydroxy-4-(4-isopropoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-330);-   4-(4-cyclobutoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-331);-   N-hydroxy-4-((6-methoxypyridin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-332);-   N-hydroxy-3-oxo-4-(quinolin-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-333);-   N-hydroxy-4-(isoquinolin-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-334);-   N-hydroxy-3-oxo-4-(quinolin-7-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-335);-   N-hydroxy-4-(isoquinolin-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-336);-   N-hydroxy-4-(isoquinolin-7-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-337);-   N-hydroxy-4-(imidazo[1,2-a]pyridin-7-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-338);-   N-hydroxy-3-oxo-4-(pyrazolo[1,3,5-a]pyridin-5-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-339);-   4-(3-chloro-2-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-340);-   4-(2-fluoro-4-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-341);-   4-(3-fluoro-5-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-342);-   4-(3-chloro-5-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-343);-   4-(4-chloro-2-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-344);-   4-(4-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-345);-   4-(4-chloro-3-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-346);-   4-(2-chloro-5-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-347);-   4-(5-chloro-2-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-348);-   4-(3-chloro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-349);-   4-(4-chloro-3-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-350);-   4-(3-chloro-4-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-351);-   4-(2-chloro-5-fluorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-352);-   4-(4-fluoro-3-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-353);-   4-(2-chloro-3-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-354);-   4-(3,5-dichlorobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-355);-   4-(2-chloro-4-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-356);-   N-hydroxy-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-357);-   N-hydroxy-4-(3-methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide    (I-358);-   N-hydroxy-3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-359);-   4-(4-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-360);-   4-(4-(dimethylamino)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-361);-   4-(4-carbamoylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamide    (I-362);-   N-hydroxy-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-363);-   N-hydroxy-4-((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-364);-   N-hydroxy-4-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-365);-   4-(3-carbamoylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-366);-   4-(3-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-367);-   4-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-368);-   N-hydroxy-4-(3-(isopropylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-369);-   N-hydroxy-3-oxo-4-(3-(pyrrolidine-1-carbonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-370);-   4-(2-fluoro-5-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-371);-   4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-372); or-   4-(2-chloro-5-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide    (I-373).

In some embodiments, the compound of Formula I comprises a compoundselected fromN-hydroxy-3-oxo-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-77);N-hydroxy-4-((6-methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-213);4-(benzo[d]oxazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-288);N-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-202);4-(benzo[d]thiazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-289);N-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-207);N-hydroxy-3-oxo-4-(quinolin-7-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-335); orN-hydroxy-4-(isoquinolin-7-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-337).

In some embodiments, the compound of Formula I comprises a compoundselected from4-(2-chloro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-259);N-hydroxy-4-(4-(oxazol-2-yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-221);4-(2-fluoro-5-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-371);N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-141);4-(2-chloro-5-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-373);4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-372);4-(2-fluoro-4-methoxybenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-160); or4-(4-chloro-2-fluorobenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-161).

In some embodiments, the compound of Formula I isN-hydroxy-3-oxo-4-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-77).

In some embodiments, the compound of Formula I isN-hydroxy-4-((6-methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-213).

In some embodiments, the compound of Formula I is4-(benzo[d]oxazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-288).

In some embodiments, the compound of Formula I isN-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-202).

In some embodiments, the compound of Formula I is4-(benzo[d]thiazol-2-ylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-289).

In some embodiments, the compound of Formula I isN-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-207).

In some embodiments, the compound of Formula I isN-hydroxy-3-oxo-4-(quinolin-7-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-335).

In some embodiments, the compound of Formula I isN-hydroxy-4-(isoquinolin-7-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-337).

In some embodiments, the compound of Formula I is4-(2-chloro-5-(trifluoromethyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-259).

In some embodiments, the compound of Formula I isN-hydroxy-4-(4-(oxazol-2-yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-221).

In some embodiments, the compound of Formula I is4-(2-fluoro-5-methoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-371).

In some embodiments, the compound of Formula I isN-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-141).

In some embodiments, the compound of Formula I is4-(2-chloro-5-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-373).

In some embodiments, the compound of Formula I is4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-372).

In some embodiments, the compound of Formula I is4-(2-fluoro-4-methoxybenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-160).

In some embodiments, the compound of Formula I is4-(4-chloro-2-fluorobenzyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-161).

In some embodiments, Y₁ is CR₃. In other embodiments, Y₂ is CR₃. Inother embodiments, Y₃ is CR₃. In other embodiments, Y₄ is CR₃. In otherembodiments, Y₁ is N. In other embodiments, Y₂ is N. In otherembodiments, Y₃ is N. In other embodiments, Y₄ is N. In otherembodiments, Y₁ is C when attached to C(O)NHOH. In other embodiments, Y₂is C when attached to C(O)NHOH. In other embodiments, Y₃ is C whenattached to C(O)NHOH. In other embodiments, Y₄ is C when attached toC(O)NHOH.

In some embodiments, W is C(R₄)(R₅). In some embodiments, W is O.

In some embodiments, R₁ is C₁-C₆ alkyl. In some embodiments, R₁ is C₁-C₆alkoxy. In some embodiments, R₁ is C₂-C₆ alkenyl. In some embodiments,R₁ is C₂-C₆ alkynyl. In some embodiments, R₁ is C₃-C₈ cycloalkyl. Insome embodiments, R₁ is C₄-C₈ cycloalkenyl. In some embodiments, R₁ isaryl. In some embodiments, R₁ is heteroaryl. In some embodiments, R₁ is3- to 8-membered heterocycle. In some embodiments, R₁ is —(CH₂)_(n)—R₄.In some embodiments, R₁ is —(CH₂)_(n)—O—(CH₂)_(p)—R₄. In someembodiments, R₁ is —S(O)₂R₄. In some embodiments, R₁ is —C(O)R₄. In someembodiments, R₁ is —C(O)N(R₄)(R₈). In some embodiments, R₁ is C₁-C₆alkyl optionally substituted with one or more —OH, halogen, oxo, —NO₂,—NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, heterocycle, aryl, heteroaryl,or R₄. In some embodiments, R₁ is C₁-C₆ alkoxy optionally substitutedwith one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl,—C₁-C₆ alkoxy, heterocycle, aryl, heteroaryl, or R₄. In someembodiments, R₁ is C₂-C₆ alkenyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,heterocycle, aryl, heteroaryl, or R₄. In some embodiments, R₁ is C₂-C₆alkynyl optionally substituted with one or more —OH, halogen, oxo, —NO₂,—NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, heterocycle, aryl, heteroaryl,or R₄. In some embodiments, R₁ is C₃-C₈ cycloalkyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, heterocycle, aryl, heteroaryl, or R₄. In someembodiments, R₁ is C₄-C₈ cycloalkenyl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,heterocycle, aryl, heteroaryl, or R₄. In some embodiments, R₁ is aryloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, heterocycle, aryl, heteroaryl, or R₄.In some embodiments, R₁ is heteroaryl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,heterocycle, aryl, heteroaryl, or R₄. In some embodiments, R₁ is 3- to8-membered heterocycle optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, heterocycle,aryl, heteroaryl, or R₄.

In some embodiments, R₂ is H. In some embodiments, R₂ is C₁-C₆ alkyl. Insome embodiments, R₂ is C₁-C₆ alkoxy. In some embodiments, R₂ is C₂-C₆alkenyl. In some embodiments, R₂ is C₂-C₆ alkynyl. In some embodiments,R₂ is C₃-C₈ cycloalkyl. In some embodiments, R₂ is C₄-C₈ cycloalkenyl.In some embodiments, R₂ is aryl. In some embodiments, R₂ is heteroaryl.In some embodiments, R₂ is 3- to 8-membered heterocycle. In someembodiments, R₂ is C₁-C₆ alkyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. Insome embodiments, R₂ is C₁-C₆ alkoxy optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy.In some embodiments, R₂ is C₂-C₆ alkenyl optionally substituted with oneor more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆alkoxy. In some embodiments, R₂ is C₂-C₆ alkynyl optionally substitutedwith one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or—C₁-C₆ alkoxy. In some embodiments, R₂ is C₃-C₈ cycloalkyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂ is C₄-C₈ cycloalkenyloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂ is aryloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂ isheteroaryl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂is 3- to 8-membered heterocycle optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy.

In some embodiments, R₂′ is H. In some embodiments, R₂′ is C₁-C₆ alkyl.In some embodiments, R₂′ is C₁-C₆ alkoxy. In some embodiments, R₂′ isC₂-C₆ alkenyl. In some embodiments, R₂′ is C₂-C₆ alkynyl. In someembodiments, R₂′ is C₃-C₈ cycloalkyl. In some embodiments, R₂′ is C₄-C₈cycloalkenyl. In some embodiments, R₂′ is aryl. In some embodiments, R₂′is heteroaryl. In some embodiments, R₂′ is 3- to 8-membered heterocycle.In some embodiments, R₂′ is C₁-C₆ alkyl optionally substituted with oneor more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆alkoxy. In some embodiments, R₂′ is C₁-C₆ alkoxy optionally substitutedwith one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or—C₁-C₆ alkoxy. In some embodiments, R₂′ is C₂-C₆ alkenyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂′ is C₂-C₆ alkynyloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In some embodiments, R₂′ is C₃-C₈cycloalkyl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In some embodiments,R₂′ is C₄-C₈ cycloalkenyl optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In someembodiments, R₂′ is aryl optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. In someembodiments, R₂′ is heteroaryl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, or —C₁-C₆ alkoxy. Insome embodiments, R₂′ is 3- to 8-membered heterocycle optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, or —C₁-C₆ alkoxy.

In some embodiments, R₂ and R₂′ may combine with the carbon to whichthey are attached to form an oxo group. In some embodiments, R₂ and R₂′can combine with the carbon to which they are attached to form C₃-C₈cycloalkyl. In some embodiments, R₂ and R₂′ can combine with the carbonto which they are attached to form 3- to 8-membered heterocycle.

In some embodiments, R₃ is hydrogen. In other embodiments, R₃ ishalogen. In other embodiments, R₃ is OH. In other embodiments, R₃ is CN.In other embodiments, R₃ is NO₂. In other embodiments, R₃ is NH₂. Inother embodiments, R₃ is C₁-C₃ alkyl. In other embodiments, R₃ is C₁-C₃alkoxy.

In some embodiments, R₄ is H. In some embodiments, R₄ is halogen. Insome embodiments, R₄ is OH. In some embodiments, R₄ is NH₂. In someembodiments, R₄ is —C(O)N(R₁₀)(R₁₁). In some embodiments, R₄ is C₁-C₆alkyl. In some embodiments, R₄ is C₁-C₆ alkoxy. In some embodiments, R₄is C₂-C₆ alkenyl. In some embodiments, R₄ is C₂-C₆ alkynyl. In someembodiments, R₄ is C₃-C₈ cycloalkyl. In some embodiments, R₄ is C₄-C₈cycloalkenyl. In some embodiments, R₄ is aryl. In some embodiments, R₄is heteroaryl. In some embodiments, R₄ is 3- to 8-membered heterocycle.In some embodiments, R₄ is C₁-C₆ alkyl optionally substituted with oneor more —OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆,—N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₄ is C₁-C₆ alkoxy optionallysubstituted with one or more —OH, R_(4′), R_(5′), halogen, oxo,—(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl. In some embodiments, R₄ is C₂-C₆alkenyl optionally substituted with one or more —OH, R_(4′), R_(5′),halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₄ is C₂-C₆ alkynyl optionally substituted with one or more—OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆,—N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₄ is C₃-C₈ cycloalkyl optionallysubstituted with one or more —OH, R_(4′), R_(5′), halogen, oxo,—(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl. In some embodiments, R₄ is C₄-C₈cycloalkenyl optionally substituted with one or more —OH, R_(4′),R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₄ is aryl optionally substituted with one or more —OH,R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇),C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₄ is heteroaryl optionally substitutedwith one or more —OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂,—OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆),—C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₄ is 3- to 8-membered heterocycleoptionally substituted with one or more —OH, R_(4′), R_(5′), halogen,oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl.

In some embodiments, R₅ is H. In some embodiments, R₅ is halogen. Insome embodiments, R₅ is OH. In some embodiments, R₅ is NH₂. In someembodiments, R₅ is —C(O)N(R₁₀)(R₁₁). In some embodiments, R₅ is C₁-C₆alkyl. In some embodiments, R₅ is C₁-C₆ alkoxy. In some embodiments, R₅is C₂-C₆ alkenyl. In some embodiments, R₅ is C₂-C₆ alkynyl. In someembodiments, R₅ is C₃-C₈ cycloalkyl. In some embodiments, R₅ is C₄-C₈cycloalkenyl. In some embodiments, R₅ is aryl. In some embodiments, R₅is heteroaryl. In some embodiments, R₅ is 3- to 8-membered heterocycle.In some embodiments, R₅ is C₁-C₆ alkyl optionally substituted with oneor more —OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆,—N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₅ is C₁-C₆ alkoxy optionallysubstituted with one or more —OH, R_(4′), R_(5′), halogen, oxo,—(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl. In some embodiments, R₅ is C₂-C₆alkenyl optionally substituted with one or more —OH, R_(4′), R_(5′),halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₅ is C₂-C₆ alkynyl optionally substituted with one or more—OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆,—N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₅ is C₃-C₈ cycloalkyl optionallysubstituted with one or more —OH, R_(4′), R_(5′), halogen, oxo,—(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl. In some embodiments, R₅ is C₄-C₈cycloalkenyl optionally substituted with one or more —OH, R_(4′),R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆,—C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇),—CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkylalkyl, arylalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₅ is aryl optionally substituted with one or more —OH,R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇),C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆,—S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₅ is heteroaryl optionally substitutedwith one or more —OH, R_(4′), R_(5′), halogen, oxo, —(CH₂)_(n)OR₆, —NO₂,—OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇), —S(O)₂R₆, —S(O)R₆, —S(R₆),—C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl, —C₁-C₆ haloalkyl, —C₁-C₆alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl, heterocycle, aryl, orheteroaryl. In some embodiments, R₅ is 3- to 8-membered heterocycleoptionally substituted with one or more —OH, R_(4′), R_(5′), halogen,oxo, —(CH₂)_(n)OR₆, —NO₂, —OR₆, —N(R₆)(R₇), C(O)OR₆, —C(O)N(R₆)(R₇),—S(O)₂R₆, —S(O)R₆, —S(R₆), —C(O)R₆, —S(O)₂N(R₆)(R₇), —CN, —C₁-C₆ alkyl,—C₁-C₆ haloalkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, arylalkyl,heterocycle, aryl, or heteroaryl.

In other embodiments, R₄ and R₅ may combine with the carbon to whichthey are attached to form an oxo group. In other embodiments, R₄ and R₅may combine with the carbon to which they are attached to form C₃-C₈cycloalkyl. In other embodiments, R₄ and R₅ may combine with the carbonto which they are attached to form 3- to 8-membered heterocycle. Inother embodiments, R₄ and R₅ may combine with the carbon to which theyare attached to form 3- to 8-membered heterocycle optionally substitutedwith one or more substituent selected from R_(4′) and R_(5′). In otherembodiments, R₄ and R₅ may combine with the nitrogen to which they areattached to form 3- to 8-membered heterocycle. In other embodiments, R₄and R₅ may combine with the nitrogen to which they are attached to form3- to 8-membered heterocycle optionally substituted with one or moresubstituent selected from R_(4′) and R_(5′).

In one embodiment, R_(4′) is H. In another embodiment, R_(4′) is —C₁-C₆alkyl. In a further embodiment, one embodiment, R_(5′) is H. In anotherembodiment, R_(5′) is —C₁-C₆ alkyl. In yet other embodiments, R_(4′) andR_(5′) together when attached to the same atom may form a C₃—Cspirocycloalkyl ring. In other embodiments R_(4′) and R_(5′) togetherwhen attached to the same atom may also form a spiroheterocycloalkyl. Inother embodiments, R_(4′) and R_(5′) together when attached to adjacentatoms may form an aryl. In other embodiments, R_(4′) and R_(5′) togetherwhen attached to adjacent atoms may form a heteroaryl. In otherembodiments, R_(4′) and R_(5′) together when attached to adjacent atomsmay form a C₃-C₈ cycloalkyl. In other embodiments, R₄, and R_(5′)together when attached to adjacent atoms form a 3- to 8-memberedheterocycle. In yet other embodiments, R_(4′) and R_(5′) together whenattached to the same atom may form a C₃—C spirocycloalkyl ringoptionally substituted with one or more OH, halogen, —C₁-C₆ alkyl orC(O)OR₆. In other embodiments R_(4′) and R_(5′) together when attachedto the same atom may also form a spiroheterocycloalkyl optionallysubstituted with one or more OH, halogen, —C₁-C₆ alkyl or C(O)OR₆. Inother embodiments, R_(4′) and R_(5′) together when attached to adjacentatoms may form an aryl optionally substituted with one or more OH,halogen, —C₁-C₆ alkyl or C(O)OR₆. In other embodiments, R_(4′) andR_(5′) together when attached to adjacent atoms may form a heteroaryloptionally substituted with one or more OH, halogen, —C₁-C₆ alkyl orC(O)OR₆. In other embodiments, R_(4′) and R_(5′) together when attachedto adjacent atoms may form a C₃-C₈ cycloalkyl optionally substitutedwith one or more OH, halogen, —C₁-C₆ alkyl or C(O)OR₆. In otherembodiments, R_(4′) and R_(5′) together when attached to adjacent atomsform a 3- to 8-membered heterocycle optionally substituted with one ormore OH, halogen, —C₁-C₆ alkyl or C(O)OR₆.

In some embodiments, R₆ is H. In some embodiments, R₆ is amino. In someembodiments, R₆ is C₁-C₆ dialkylamino. In some embodiments, R₆ is C₁-C₆alkylamino. In some embodiments, R₆ is —S(O)₂N(R₈)(R₉). In someembodiments, R₆ is C₁-C₆ alkyl. In some embodiments, R₆ is C₁-C₆ alkoxy.In some embodiments, R₆ is C₂-C₆ alkenyl. In some embodiments, R₆ isC₂-C₆ alkynyl. In some embodiments, R₆ is C₃-C₈ cycloalkyl. In someembodiments, R₆ is C₄-C₈ cycloalkenyl. In some embodiments, R₆ is aryl.In some embodiments, R₆ is heteroaryl. In some embodiments, R₆ is 3- to8-membered heterocycle. In some embodiments, R₆ is —S(O)₂R₈. In someembodiments, R₆ is —C(O)R₈. In some embodiments, R₆ is —C(O)OR₈. In someembodiments, R₆ is s₈. In some embodiments, R₆ is —S(O)N(R₈)(R₉). Insome embodiments, R₆ is C₁-C₆ alkyl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle,aryl, heteroaryl. In some embodiments, R₆ is C₁-C₆ alkoxy optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, heteroaryl. In some embodiments, R₆ isC₂-C₆ alkenyl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, heteroaryl. In someembodiments, R₆ is C₂-C₆ alkynyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,heteroaryl. In some embodiments, R₆ is C₃-C₈ cycloalkyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, heteroaryl. In some embodiments, R₆ isC₄-C₈ cycloalkenyl optionally substituted with one or more —OH, halogen,oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino,C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, heteroaryl.In some embodiments, R₆ is aryl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,heteroaryl. In some embodiments, R₆ is heteroaryl optionally substitutedwith one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl,—C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl,heterocycle, aryl, heteroaryl. In some embodiments, R₆ is 3- to8-membered heterocycle optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,heteroaryl.

In some embodiments, R₇ is H. In some embodiments, R₇ is amino. In someembodiments, R₇ is C₁-C₆ dialkylamino. In some embodiments, R₇ is C₁-C₆alkylamino. In some embodiments, R₇ is —S(O)₂N(R₈)(R₉). In someembodiments, R₇ is C₁-C₆ alkyl. In some embodiments, R₇ is C₁-C₆ alkoxy.In some embodiments, R₇ is C₂-C₆ alkenyl. In some embodiments, R₇ isC₂-C₆ alkynyl. In some embodiments, R₇ is C₃-C₈ cycloalkyl. In someembodiments, R₇ is C₄-C₈ cycloalkenyl. In some embodiments, R₇ is aryl.In some embodiments, R₇ is heteroaryl. In some embodiments, R₇ is 3- to8-membered heterocycle. In some embodiments, R₇ is —S(O)₂R₈. In someembodiments, R₇ is —C(O)R₈. In some embodiments, R₇ is —C(O)OR₈. In someembodiments, R₇ is s₈. In some embodiments, R₇ is —S(O)N(R₈)(R₉). Insome embodiments, R₇ is C₁-C₆ alkyl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle,aryl, or heteroaryl. In some embodiments, R₇ is C₁-C₆ alkoxy optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, heteroaryl. In some embodiments, R₇ isC₂-C₆ alkenyl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. Insome embodiments, R₇ is C₂-C₆ alkynyl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle,aryl, or heteroaryl. In some embodiments, R₇ is C₃-C₈ cycloalkyloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₇ is C₄-C₈ cycloalkenyl optionally substituted with one ormore —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy,C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle,aryl, or heteroaryl. In some embodiments, R₇ is aryl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl. In some embodiments, R₇is heteroaryl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. Insome embodiments, R₇ is 3- to 8-membered heterocycle optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl.

In some embodiments, R₆ and R₇ together with the atom to which they areattached may form a C₃-C₈ cycloalkyl. In other embodiments, R₆ and R₇together with the atom to which they are attached may form a 3- to8-membered heterocycle. In some embodiments, R₆ and R₇ together with theatom to which they are attached may form a C₃-C₈ cycloalkyl optionallysubstituted with one or more halogen, oxo or C₁-C₆ alkyl. In otherembodiments, R₆ and R₇ together with the atom to which they are attachedmay form a 3- to 8-membered heterocycle optionally substituted with oneor more halogen, oxo or C₁-C₆ alkyl.

In some embodiments, R₈ is C₁-C₆ alkyl. In some embodiments, R₈ is C₂-C₆alkenyl. In some embodiments, R₈ is C₂-C₆ alkynyl. In some embodiments,R₈ is C₃-C₈ cycloalkyl. In some embodiments, R₈ is C₄-C₈ cycloalkenyl.In some embodiments, R₈ is heteroaryl. In some embodiments, R₈ is 3- to8-membered heterocycle. In some embodiments, R₈ is C₁-C₆ alkyloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₈ is C₂-C₆ alkenyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,or heteroaryl. In some embodiments, R₈ is C₂-C₆ alkynyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl. In some embodiments, R₈is C₃-C₈ cycloalkyl optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,or heteroaryl. In some embodiments, R₈ is C₄-C₈ cycloalkenyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl. In some embodiments, R₈is heteroaryl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. Insome embodiments, R₈ is 3- to 8-membered heterocycle optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl.

In some embodiments, R₉ is C₁-C₆ alkyl. In some embodiments, R₉ is C₂-C₆alkenyl. In some embodiments, R₉ is C₂-C₆ alkynyl. In some embodiments,R₉ is C₃-C₈ cycloalkyl. In some embodiments, R₉ is C₄-C₈ cycloalkenyl.In some embodiments, R₉ is heteroaryl. In some embodiments, R₉ is 3- to8-membered heterocycle. In some embodiments, R₉ is C₁-C₆ alkyloptionally substituted with one or more —OH, halogen, oxo, —NO₂, —NH₂,—CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino,C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. In someembodiments, R₉ is C₂-C₆ alkenyl optionally substituted with one or more—OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,or heteroaryl. In some embodiments, R₉ is C₂-C₆ alkynyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl. In some embodiments, R₉is C₃-C₈ cycloalkyl optionally substituted with one or more —OH,halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆alkylamino, C₁-C₆ dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl,or heteroaryl. In some embodiments, R₉ is C₄-C₈ cycloalkenyl optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl. In some embodiments, R₉is heteroaryl optionally substituted with one or more —OH, halogen, oxo,—NO₂, —NH₂, —CN, —C₁-C₆ alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆dialkylamino, C₁-C₆ hydroxyalkyl, heterocycle, aryl, or heteroaryl. Insome embodiments, R₉ is 3- to 8-membered heterocycle optionallysubstituted with one or more —OH, halogen, oxo, —NO₂, —NH₂, —CN, —C₁-C₆alkyl, —C₁-C₆ alkoxy, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, C₁-C₆hydroxyalkyl, heterocycle, aryl, or heteroaryl.

In another embodiment, R₁₀ is H. In some embodiments, R₁₀ is C₁-C₆alkyl. In some embodiments, R₁₀ is aryl. In some embodiments, R₁₀ isarylalkyl. In some embodiments, R₁₀ is 3- to 8-membered heterocycle. Inanother embodiment, R₁₀ is H. In some embodiments, R₁₀ is C₁-C₆ alkyloptionally substituted with one or more halogen, C₁-C₆ alkyl, or C₁-C₆alkoxy. In some embodiments, R₁₀ is aryl optionally substituted with oneor more halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In some embodiments, R₁₀is arylalkyl optionally substituted with one or more halogen, C₁-C₆alkyl, or C₁-C₆ alkoxy. In some embodiments, R₁₀ is 3- to 8-memberedheterocycle optionally substituted with one or more halogen, C₁-C₆alkyl, or C₁-C₆ alkoxy.

In another embodiment, R₁₁ is H. In some embodiments, R₁₁ is C₁-C₆alkyl. In some embodiments, R₁₁ is aryl. In some embodiments, R₁₁ isarylalkyl. In some embodiments, R₁₁ is 3- to 8-membered heterocycle. Inanother embodiment, R₁₁ is H. In some embodiments, R₁₁ is C₁-C₆ alkyloptionally substituted with one or more halogen, C₁-C₆ alkyl, or C₁-C₆alkoxy. In some embodiments, R₁₁ is aryl optionally substituted with oneor more halogen, C₁-C₆ alkyl, or C₁-C₆ alkoxy. In some embodiments, R₁₁is arylalkyl optionally substituted with one or more halogen, C₁-C₆alkyl, or C₁-C₆ alkoxy. In some embodiments, R₁₁ is 3- to 8-memberedheterocycle optionally substituted with one or more halogen, C₁-C₆alkyl, or C₁-C₆ alkoxy.

In other embodiments, R₁₀ and R₁₁ may combine to form a 3- to 8-memberedheterocycle. In other embodiments, R₁₀ and R₁₁ may combine to form a 3-to 8-membered heterocycle optionally substituted with one or more R₁₂.

In some embodiments, R₁₂ is H. In some embodiments, R₁₂ is C₁-C₆ alkyl.In yet other embodiments, two adjacent R₁₂ can combine to form an aryl.In yet other embodiments, two adjacent R₁₂ can combine to form aheteroaryl.

In some embodiments, n is 1. In other embodiments, n is 2. In someembodiments, n is 3. In other embodiments, n is 4. In some embodiments,n is 5. In other embodiments, n is 6. In some embodiments, p is 0. Insome embodiments, p is 1. In some embodiments, p is 2.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₁ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₂ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₃ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₄ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₁ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₂ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₃ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₄ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₁ is C when attachedto C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ andY₂ is C when attached to C(O)NHOH. In other embodiments, R₁ is—(CH₂)_(n)—R₄, X is S(O)₂ and Y₃ is C when attached to C(O)NHOH. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₄ is C whenattached to C(O)NHOH.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₂ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₃ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₄ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₂ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₃ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₄ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is C when attached toC(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is O and Y₂ is Cwhen attached to C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, Xis O and Y₃ is C when attached to C(O)NHOH. In other embodiments, R₁ is—(CH₂)_(n)—R₄, X is O and Y₄ is C when attached to C(O)NHOH.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁ is CR₃.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₂ is CR₃.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₃ is CR₃.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₄ is CR₃.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁ is N.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₂ is N.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₃ is N.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₄ is N.In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁ is Cwhen attached to C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, Xis C(R₄)(R₅) and Y₂ is C when attached to C(O)NHOH. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₃ is C whenattached to C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X isC(R₄)(R₅) and Y₄ is C when attached to C(O)NHOH.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₁ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₂ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₃ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₄ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₁ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₂ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₃ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₄ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₁ is C when attached toC(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₂ isC when attached to C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄,X is S(O) and Y₃ is C when attached to C(O)NHOH. In other embodiments,R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₄ is C when attached to C(O)NHOH.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₁ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₂ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₃ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₄ is CR₃. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₁ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₂ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₃ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₄ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₁ is C when attached toC(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is S and Y₂ is Cwhen attached to C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, Xis S and Y₃ is C when attached to C(O)NHOH. In other embodiments, R₁ is—(CH₂)_(n)—R₄, X is S and Y₄ is C when attached to C(O)NHOH.

In some embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₁ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₂ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₃ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₄ is CR₃. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₁ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₂ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₃ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₄ is N. In otherembodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₁ is C when attachedto C(O)NHOH. In other embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) andY₂ is C when attached to C(O)NHOH. In other embodiments, R₁ is—(CH₂)_(n)—R₄, X is C(═O) and Y₃ is C when attached to C(O)NHOH. Inother embodiments, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₄ is C whenattached to C(O)NHOH.

In some embodiments, X is S(O)₂ and Y₁ is CR₃. In other embodiments, Xis S(O)₂ and Y₂ is CR₃. In other embodiments, X is S(O)₂ and Y₃ is CR₃.In other embodiments, X is S(O)₂ and Y₄ is CR₃. In other embodiments, Xis S(O)₂ and Y₁ is N. In other embodiments, X is S(O)₂ and Y₂ is N. Inother embodiments, X is S(O)₂ and Y₃ is N. In other embodiments, X isS(O)₂ and Y₄ is N. In other embodiments, X is S(O)₂ and Y₁ is C whenattached to C(O)NHOH. In other embodiments, X is S(O)₂ and Y₂ is C whenattached to C(O)NHOH. In other embodiments, X is S(O)₂ and Y₃ is C whenattached to C(O)NHOH. In other embodiments, X is S(O)₂ and Y₄ is C whenattached to C(O)NHOH.

In some embodiments, X is O and Y₁ is CR₃. In other embodiments, X is Oand Y₂ is CR₃. In other embodiments, X is O and Y₃ is CR₃. In otherembodiments, X is O and Y₄ is CR₃. In other embodiments, X is O and Y₁is N. In other embodiments, X is O and Y₂ is N. In other embodiments, Xis O and Y₃ is N. In other embodiments, X is O and Y₄ is N. In otherembodiments, X is O and Y₁ is C when attached to C(O)NHOH. In otherembodiments, X is O and Y₂ is C when attached to C(O)NHOH. In otherembodiments, X is O and Y₃ is C when attached to C(O)NHOH. In otherembodiments, X is O and Y₄ is C when attached to C(O)NHOH.

In some embodiments, X is C(R₄)(R₅) and Y₁ is CR₃. In other embodiments,X is C(R₄)(R₅) and Y₂ is CR₃. In other embodiments, X is C(R₄)(R₅) andY₃ is CR₃. In other embodiments, X is C(R₄)(R₅) and Y₄ is CR₃. In otherembodiments, X is C(R₄)(R₅) and Y₁ is N. In other embodiments, X isC(R₄)(R₅) and Y₂ is N. In other embodiments, X is C(R₄)(R₅) and Y₃ is N.In other embodiments, X is C(R₄)(R₅) and Y₄ is N. In other embodiments,X is C(R₄)(R₅) and Y₁ is C when attached to C(O)NHOH. In otherembodiments, X is C(R₄)(R₅) and Y₂ is C when attached to C(O)NHOH. Inother embodiments, X is C(R₄)(R₅) and Y₃ is C when attached to C(O)NHOH.In other embodiments, X is C(R₄)(R₅) and Y₄ is C when attached toC(O)NHOH.

In some embodiments, X is S(O) and Y₁ is CR₃. In other embodiments, X isS(O) and Y₂ is CR₃. In other embodiments, X is S(O) and Y₃ is CR₃. Inother embodiments, X is S(O) and Y₄ is CR₃. In other embodiments, X isS(O) and Y₁ is N. In other embodiments, X is S(O) and Y₂ is N. In otherembodiments, X is S(O) and Y₃ is N. In other embodiments, X is S(O)) andY₄ is N. In other embodiments, X is S(O) and Y₁ is C when attached toC(O)NHOH. In other embodiments, X is S(O) and Y₂ is C when attached toC(O)NHOH. In other embodiments, X is S(O) and Y₃ is C when attached toC(O)NHOH. In other embodiments, X is S(O) and Y₄ is C when attached toC(O)NHOH.

In some embodiments, X is S and Y₁ is CR₃. In other embodiments, X is Sand Y₂ is CR₃. In other embodiments, X is S and Y₃ is CR₃. In otherembodiments, X is S and Y₄ is CR₃. In other embodiments, X is S and Y₁is N. In other embodiments, X is S and Y₂ is N. In other embodiments, Xis S and Y₃ is N. In other embodiments, X is S and Y₄ is N. In otherembodiments, X is S and Y₁ is C when attached to C(O)NHOH. In otherembodiments, X is S and Y₂ is C when attached to C(O)NHOH. In otherembodiments, X is S and Y₃ is C when attached to C(O)NHOH. In otherembodiments, X is S and Y₄ is C when attached to C(O)NHOH.

In some embodiments, X is C(═O) and Y₁ is CR₃. In other embodiments, Xis C(═O) and Y₂ is CR₃. In other embodiments, X is C(═O) and Y₃ is CR₃.In other embodiments, X is C(═O) and Y₄ is CR₃. In other embodiments, Xis C(═O) and Y₁ is N. In other embodiments, X is C(═O) and Y₂ is N. Inother embodiments, X is C(═O) and Y₃ is N. In other embodiments, X isC(═O) and Y₄ is N. In other embodiments, X is C(═O) and Y₁ is C whenattached to C(O)NHOH. In other embodiments, X is C(═O) and Y₂ is C whenattached to C(O)NHOH. In other embodiments, X is C(═O) and Y₃ is C whenattached to C(O)NHOH. In other embodiments, X is C(═O) and Y₄ is C whenattached to C(O)NHOH.

In some embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₁ isCR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ andY₂ is CR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂and Y₃ is CR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X isS(O)₂ and Y₄ is CR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄,X is S(O)₂ and Y₁ is N. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is S(O)₂ and Y₂ is N. In other embodiments, n is 1, R₁is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₃ is N. In other embodiments, n is 1,R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₄ is N. In other embodiments, n is1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₁ is C when attached toC(O)NHOH. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂and Y₂ is C when attached to C(O)NHOH. In other embodiments, n is 1, R₁is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₃ is C when attached to C(O)NHOH. Inother embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O)₂ and Y₄ is Cwhen attached to C(O)NHOH.

In some embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₂ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₃ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₄ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₂ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₃ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₄ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₁ is Cwhen attached to C(O)NHOH. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is O and Y₂ is C when attached to C(O)NHOH. In otherembodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is O and Y₃ is C whenattached to C(O)NHOH. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄,X is O and Y₄ is C when attached to C(O)NHOH.

In some embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁is CR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X isC(R₄)(R₅) and Y₂ is CR₃. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₃ is CR₃. In other embodiments, n is1, R1 is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₄ is CR₃. In otherembodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁ is N. Inother embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₂ isN. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) andY₃ is N. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X isC(R₄)(R₅) and Y₄ is N. In other embodiments, n is 1, R1 is—(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₁ is C when attached to C(O)NHOH. Inother embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₂ isC when attached to C(O)NHOH. In other embodiments, n is 1, R1 is—(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₃ is C when attached to C(O)NHOH. Inother embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is C(R₄)(R₅) and Y₄ isC when attached to C(O)NHOH.

In some embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S(O) and Y₁ isCR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₂is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S(O) andY₃ is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S(O)and Y₄ is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X isS(O) and Y₁ is N. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, Xis S(O) and Y₂ is N. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄,X is S(O) and Y₃ is N. In other embodiments, n is 1, R1 is—(CH₂)_(n)—R₄, X is S(O) and Y₄ is N. In other embodiments, n is 1, R₁is —(CH₂)_(n)—R₄, X is S(O) and Y₁ is C when attached to C(O)NHOH. Inother embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S(O) and Y₂ is Cwhen attached to C(O)NHOH. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is S(O) and Y₃ is C when attached to C(O)NHOH. In otherembodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S(O) and Y₄ is C whenattached to C(O)NHOH.

In some embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S and Y₁ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₂ is CR₃.In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S and Y₃ is CR₃.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₄ is CR₃.In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is S and Y₁ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₂ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₃ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₄ is N.In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₁ is Cwhen attached to C(O)NHOH. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is S and Y₂ is C when attached to C(O)NHOH. In otherembodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is S and Y₃ is C whenattached to C(O)NHOH. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄,X is S and Y₄ is C when attached to C(O)NHOH.

In some embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₁ isCR₃. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is C(═O) andY₂ is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X is C(═O)and Y₃ is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄, X isC(═O) and Y₄ is CR₃. In other embodiments, n is 1, R1 is —(CH₂)_(n)—R₄,X is C(═O) and Y₁ is N. In other embodiments, n is 1, R₁ is—(CH₂)_(n)—R₄, X is C(═O) and Y₂ is N. In other embodiments, n is 1, R1is —(CH₂)_(n)—R₄, X is C(═O) and Y₃ is N. In other embodiments, n is 1,R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₄ is N. In other embodiments, n is1, R₁ is —(CH₂)_(n)—R₄, X is C(═O) and Y₁ is C when attached toC(O)NHOH. In other embodiments, n is 1, R₁ is —(CH₂)_(n)—R₄, X is C(═O)and Y₂ is C when attached to C(O)NHOH. In other embodiments, n is 1, R1is —(CH₂)_(n)—R₄, X is C(═O) and Y₃ is C when attached to C(O)NHOH. Inother embodiments, n is 1, R1 is —(CH2)_(n)-R4, X is C(═O) and Y4 is Cwhen attached to C(O)NHOH.

In another embodiment of the invention, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present invention includes bothpossible stereoisomers (unless specified in the synthesis) and includesnot only racemic compounds but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994, herein incorporatedby reference in its entirety).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below.

Methods of Using the Disclosed Compounds

One aspect of the present invention relates to a method of modulatingHDAC8, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method ofinhibiting HDAC8, comprising administering to a patient in need thereofa therapeutically effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method ofinhibiting HDAC8, comprising administering to a patient in need thereofa therapeutically effective amount of the pharmaceutical compositioncomprising a compound of Formula (I).

Another aspect of the present invention relates to a method of treating,preventing, inhibiting, or eliminating a disease or disorder in apatient associated with the inhibition of HDAC8, the method comprisingadministering a therapeutically effective amount of a compound ofFormula (I).

One therapeutic use of the compounds of the present invention is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include colon cancer, lung cancer, neuroblastoma, ovarian cancer,hepatocellular carcinoma, gastric cancer, prostate cancer, pancreaticcancer, renal cancer and leukemias such as acute myeloid leukemia andacute lymphoblastic leukemia. Additional cancer types include T-celllymphoma (e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma),B-cell lymphoma and multiple myeloma. In other embodiments, treatingproliferative diseases or disorders can include any cancer where thereis evidence of an increase in Treg/effector T cell ratio or in anabsolute Treg number, either in the periphery or in the tumormicroenvironment or tertiary lymphoid structures, or increasedexpression of T cell tolerance-related genes. Such proliferativediseases or disorders can include but are not limited to: any Krasmutant carrying tumor (Zdanov, S. et. al. (2016) Cancer Immunol Res. 4,354-65); renal cell carcinoma; lung carcinoma; cervical cancer; prostatecancer; ovarian cancer; head and neck cancer; lymphoma; colorectalcancer, non small cell lung carcinoma; breast cancers (Gobert, M. et al.(2009) Cancer Res. 69, 2000-2009); and bladder cancer.

One therapeutic use of the compounds of the present invention is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders and diseasescan include but are not limited to epilepsy, attention deficit disorder(ADD), Alzheimer's disease, Parkinson's Disease, Huntington's Disease,Muscular dystrophy, essential tremor, central nervous system traumacaused by tissue injury, oxidative stress-induced neuronal or axomaldegeneration, ALS, and multiple sclerosis.

Another therapeutic use of the compounds of the present invention isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-13, andincreased expression of the FOXP3 transcription factor. In someembodiments, the inflammatory diseases include fibrosis or fibroticdiseases. Types of fibrotic diseases include but are not limited to lungfibrosis or pulmonary fibrosis, Liver fibrosis; Heart fibrosis;Mediastinal fibrosis; Retroperitoneal cavity fibrosis; Bone marrowfibrosis; Skin fibrosis; and Scleroderma or systemic sclerosis.

Another therapeutic use of the compounds of the present invention isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include but are not limited to rheumatoidarthritis, Crohn's disease, type-1 diabetes, systemic juvenileidiopathic arthritis; inflammatory bowel disease; allografttransplantation; eczema, psoriasis, idiopathic thrombocytopenic purpra,autoimmune thrombocytopenia, acquired immune thrombocytopenia, autimmuneneutropenia, autoimmune hemolyitic anemia, parvovirus B19-associated redcell aplasia, acquired antifactor VIII autoimmunity, acquired vonWillebrand disease, monoclonal gammopathy, aplastic anemia, pure redcell aplasia, Diamond-Blackfan anemia, hemolytic disease of the newborn,immune mediated-refractoriness to platelet transfusion, hemolytic uremicsyndrome, Evan's syndrome, Guillain-Barre syndrome, chronicdemyelinating polyradiculoneuropathy, paraproteinemic IgM demyelinatingpolyneuropathy, Lamber-Eaton myasthenic syndeom, myasthenia gravis,multifocal motor neuropathy, stiff man syndrome, paraneoplasticencephalomyelitis, sensory neuropathy with anti-Hu antibodies, myelitis,autoimmune diabetic neuropathy, acute idiopathic neuropathy, toxicepidermal necrolysis, gangrene, granuloma, pemphigus vulgaris, bullouspemphigoid, vitiligo, scleroderma, atomic dermatis, systemic and diffusesclerosis, primary biliary cirrhosis, Celiac disease, dermatitisherpetiformis, cryptogenic cirrhosis, reactive arthritis, Hashimoto'sthryroditis, Wegner's granulomoatosis, micropolyarterits, Churg-Strausssyndrome Type I and Type II autoimmune polygalndular syndromes, linearIgA disease, epidermolysis bullosa acquisita, erythema nodosa,pemphigoid gestationis, cicatricial pemphigoid, mixed essentialcryoglobulinemia, chronic bullous disease of childhood, Goodpasture'ssyndrome, sclerosis cholangitis, ankylosing spondylitis, Bechet'ssyndrome temporal arteritis, Takayasu's arteritis, autoimmune urticaria,and Kawasaki's disease.

Another therapeutic use of the compounds of the present invention isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus.Bacterial infections include, but are not limited to streptococcusinfections, mycobacterial infections, bacillus infections, Salmonellainfections, Vibrio infections, spirochete infections, and Neisseriainfections. Viral infections include, but are not limited to herpesvirus infections, hepatitis virus infections, west nile virusinfections, flavivrus infections, influenza virus infections, rhinovirusinfections, papillomavirus infections, paromyxovirus infections,parainfluenza virus infections, and retrovirus infections. In particularembodiments, the compounds of the present invention are useful fortreating infections which result in an inflammatory cytokine burst.Nonlimiting examples of such infections include Ebola and other viralhemorghagic fever-causing viruses, and Malaria.

Another therapeutic use of the compounds of the present invention isalso to treat and/or prevent allergy and unwanted immune responsesassociated with allergy. A non-limiting list of allergies and relatedconditions includes, pollen allergy (e.g. Japanese Cedar Pollen), moldallergy, food allergies (including, but not limited to peanut, tree nut,milk, soy, gluten, and egg allergies), animal allergies (e.g. allergiesto dogs, cats, rabbits), dust mite allergy, atopic dermatitis, allergicrhinitis, allergic otitis, allergic asthma, dry eye, ocular allergy,allergic urticaria, contact dermatitis, anaphalaxis, eosinophilicesophagitis.

Yet another therapeutic use of the compounds of the present invention isalso to treat metabolic diseases or disorders. Metabolic diseases can becharacterized as abnormalities in the way that a subject stores energy.Metabolic disorders can include but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, non-alcoholic fattyliver disease and heart failure.

Yet another therapeutic use of the compounds of the present invention isalso to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include but are not limitedto anemia, multiple myeloma, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present invention isalso to prevent and/or treat transplant rejection. Tissues that aretransplanted include (but are not limited to) whole organs such askidney, liver, heart, lung; organ components such as skin grafts and thecornea of the eye; and cell suspensions such as bone marrow cells andcultures of cells selected and expanded from bone marrow or circulatingblood, and whole blood transfusions.

Yet another therapeutic use of the compounds of the present invention isalso to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, Brain infarct after cerebral artery occlusion;atherosclerosis, peripheral artery disease, cardiac hypertrophy, cardiacarrhythmias, stroke, and heart failure.

Another therapeutic use of the compounds of the present invention is forpurging the reservoir of latently infected memory CD4+ T cells in HIV+patients (Matalon, et al., Mol Med. 2011; 17(5-6): 466-472).

The disclosed compounds can be administered in effective amounts totreat or prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoylresidues. Furthermore, the disclosed compounds can be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, disclosed compoundsare not covalently bound to a polymer, e.g., a polycarboxylic acidpolymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present invention can inhibit HDACs such as HDAC8 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

Examples

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present invention includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, in particularHDAC8. For instance, the present invention features a unique class ofsmall molecule therapeutic agents of Formula I. The compounds weredesigned by using crystal structure information of HDAC ligand-proteincomplexes as well as advanced computational chemistry tools. Thesetechniques led to the development of new chemical scaffolds that wereiteratively refined to optimize key recognition features between theligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

-   Ac₂O acetic anhydride-   Boc tert-butoxycarbonyl-   DCE 1,2-dichloroethane-   DCM dichloromethane or methylene chloride-   DIPEA N,N-diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   dppf bis(diphenylphosphino)ferrocene-   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et₃N triethylamine-   EtOAc ethyl acetate-   EtOH ethanol-   h hours-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HCl hydrogen chloride-   HOBT Hydroxybenzotriazole-   HPLC high performance liquid chromatography-   (i-Pr)₂NEt N,N-diisopropylethylamine-   LC/MS liquid chromatography/mass spectrometry-   K₂CO₃ potassium carbonate-   MS mass spectrometry-   NB S N-bromosuccinimide-   Ph₃P triphenylphosphine-   PhCHO benzaldehyde-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium-   p-TsOH para-toluenesulfonic acid-   rt room temperature-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl    Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, all materials were obtained from commercialsuppliers and were used without further purification. Anhydrous solventswere obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly.All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere.

Unless otherwise noted, mass-triggered HPLC purification and/or purityand low resolution mass spectral data were measured using either: (1)Waters Acquity ultra performance liquid chromatography (UPLC) system(Waters Acquity UPLC with Sample Organizer and Waters Micromass ZQ MassSpectrometer) with UV detection at 220 nm and a low resonanceelectrospray positive ion mode (ESI) (Column: Acquity UPLC BEH C₁₈ 1.7μm 2.1×50 mm; gradient: 5-100% Solvent B (95/5/0.09%:Acetonitrile/Water/Formic Acid) in Solvent A (95/5/0.1%: 10 mM AmmoniumFormate/Acetonitrile/Formic Acid) for 2.2 min then 100-5% Solvent B inSolvent A for 0.01 min then hold at 5% Solvent B in Solvent A for 0.29min) or (2) Waters HT2790 Alliance high performance liquidchromatography (HPLC) system (Waters 996 PDA and Waters ZQ Single QuadMass Spectrometer) with UV detection at 220 nm and 254 nm and a lowresonance electrospray ionization (positive/negative) mode (ESI)(Column: XBridge Phenyl or C18, 5 μm 4.6×50 mm; gradient: 5-95% SolventB (95% methanol/5% water with 0.1% Formic Acid) in Solvent A (95%water/5% methanol with 0.1% Formic Acid) for 2.5 min then hold at 95%Solvent B in Solvent A for 1 min (purity and low resolution MS only).

Example 1—Intermediate 1: methyl6-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Step-1: 2-tert-butyl 6-methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate

Into a 500-mL 3-necked round-bottom flask was placed a solution ofmethyl 3-amino-4-hydroxybenzoate (10 g, 59.82 mmol) and potassiumcarbonate (25 g, 180.88 mmol) in N,N-dimethylformamide (150 mL). Thiswas followed by the dropwise addition of tert-butyl2,3-dibromopropanoate (19 g, 65.98 mmol) with stirring. The resultingsolution was stirred for 4 h at room temperature and overnight at 70° C.The reaction was then quenched by the addition of 500 mL of water. Theresulting solution was extracted with 3×200 mL of ethyl acetate, washedwith 3×300 mL of brine, dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with 1:3, ethyl acetate/petroleumether). The collected fractions were concentrated to give 2-tert-butyl6-methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate (9.4 g,54%) as an off-white solid. MS: (ES, m/z): 294 [M+H]⁺.

Step-2: 2-tert-butyl 6-methyl4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate

Into a 50-mL 3-necked round-bottom flask was placed a solution of2-tert-butyl 6-methyl 3,4-dihydro-2H-1,4-benzoxazine-2,6-dicarboxylate(2 g, 6.82 mmol), potassium carbonate (2.83 g, 20.48 mmol) and methyliodide (2.9 g, 20.42 mmol) in N,N-dimethylformamide (20 mL). Theresulting mixture was stirred overnight at 70° C. The reaction was thenquenched by the addition of 100 mL of water. The resulting solution wasextracted with 3×50 mL of ethyl acetate, washed with 3×50 mL of brine,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with 1:4, ethyl acetate/petroleum ether). The collectedfractions were concentrated to give 2-tert-butyl 6-methyl4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate (1.7 g,81%) as an off-white solid. MS: (ES, m/z): 308 [M+H]⁺.

Step-3:6-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Into a 100-mL round-bottom flask was placed 2-tert-butyl 6-methyl4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2,6-dicarboxylate (1 g, 3.25mmol), dichloromethane (25 mL) and trifluoroacetic acid (5 mL). Theresulting solution was stirred overnight at room temperature and thenconcentrated under vacuum to give6-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (1.2 g) as a gray solid which was used without any purification.MS: (ES, m/z): 252 [M+H]⁺.

Example 2—Intermediate 2:4-benzyl-6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Step-1: 2-tert-butyl 6-methyl4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate

Into a 50-mL 3-necked round-bottom flask was placed a solution of2-tert-butyl 6-methyl 3,4-dihydro-2H-1,4-benzoxazine-2,6-dicarboxylate(2 g, 6.82 mmol) and potassium carbonate (2.83 g, 20.48 mmol) inN,N-dimethylformamide (20 mL). This was followed by the dropwiseaddition of benzyl bromide (2.3 g, 13.45 mmol) with stirring at 0° C.The resulting solution was stirred overnight at 70° C. The reaction wasthen quenched by the addition of 100 mL of water. The resulting solutionwas extracted with 3×50 mL of ethyl acetate, washed with 3×50 mL ofbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel, eluting with ethyl acetate/petroleum ether (1:4). Thecollected fractions were concentrated to give 2-tert-butyl 6-methyl4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxylate (1.2 g,46%) of title compound as an off-white solid. MS: (ES, m/z): 384 [M+H]⁺.

Step-2:4-benzyl-6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Into a 100-mL round-bottom flask was placed 2-tert-butyl 6-methyl4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2,6-dicarboxylate (1.2 g, 3.13mmol), dichloromethane (25 mL) and trifluoroacetic acid (5 mL). Theresulting solution was stirred overnight at room temperature and thenconcentrated under vacuum to give4-benzyl-6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (1.5 g) as brown oil which was used without any purification. MS:(ES, m/z): 328 [M+H]⁺.

Example 3—Intermediate 3:7-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Step-1: tert-butyl 2,3-dibromopropanoate

Into a 1000-mL, 3-necked round-bottom flask was placed a solution oftert-butyl prop-2-enoate (64 g, 499 mmol) in chloroform (200 mL). Thiswas followed by the dropwise addition of a solution of bromine (80 g,500 mmol) in chloroform (100 mL) with stirring. The resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched by the addition of sodium sulfite solution (1 M, 200 mL). Theresulting solution was extracted with 2×200 mL of dichloromethane,washed with 400 mL of brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to give tert-butyl2,3-dibromopropanoate (130 g) as colorless oil which was used directlyfor the next step without any purification.

Step-2: 2-tert-butyl 7-methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate

Into a 250-mL 3-necked round-bottom flask was placed methyl4-amino-3-hydroxybenzoate (10 g, 59.82 mmol), acetone (100 mL) andpotassium carbonate (24.8 g, 179.44 mmol). This was followed by thedropwise addition of tert-butyl 2,3-dibromopropanoate (19.9 g, 69.10mmol) with stirring. The resulting mixture was stirred overnight at 56°C. in an oil bath. The reaction was then quenched by the addition of 200mL of water. The resulting solution was extracted with 3×300 mL ofdichloromethane, washed with 100 mL of brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residuepurified via column chromatography on silica gel, eluting with ethylacetate/petroleum ether (1:2). The collected fractions were concentratedto give 2-tert-butyl 7-methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate (3.7 g, 21%) as a white solid. MS:(ES, m/z): 294 [M+H]⁺.

Step-3: 2-tert-butyl 7-methyl4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate

Into a 50-mL sealed tube was placed 2-tert-butyl 7-methyl3,4-dihydro-2H-1,4-benzoxazine-2,7-dicarboxylate (1.0 g, 3.41 mmol),N,N-dimethylformamide (10 mL), potassium carbonate (1.41 g, 10.2 mmol)and methyl iodide (1.45 g, 310.2 mmol). The resulting solution wasstirred overnight at 70° C. in an oil bath. The reaction was cooled toroom temperature and then quenched by the addition of 100 mL of water.The resulting solution was extracted with 3×150 mL of ethyl acetate,washed with 2×100 mL of brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel, eluting with ethylacetate/petroleum ether (1:5). The collected fractions were concentratedto give 2-tert-butyl 7-methyl4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate (400 mg,38%) as a yellow solid. MS: (ES, m/z): 308 [M+H]⁺.

Step-4:7-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Into a 50-mL round-bottom flask, was placed 2-tert-butyl 7-methyl4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2,7-dicarboxylate (400 mg, 1.30mmol), dichloromethane (5 mL) and trifluoroacetic acid (1 mL). Theresulting solution was stirred overnight at room temperature, and thenconcentrated under vacuum to give7-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (380 mg) as a brown solid which was used without any purification.MS: (ES, m/z): 252 [M+H]⁺.

Example 4—Intermediate 4:4-benzyl-7-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Step-1: 2-tert-butyl 7-methyl4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate

Into a 50-mL sealed tube was placed 2-tert-butyl 7-methyl3,4-dihydro-2H-1,4-benzoxazine-2,7-dicarboxylate (1.0 g, 3.41 mmol),N,N-dimethylformamide (10 mL), potassium carbonate (1.41 g, 10.20 mmol)and benzyl bromide (1.17 g, 6.84 mmol). The resulting mixture wasstirred overnight at 70° C. in an oil bath. The reaction was then cooledto room temperature and quenched by the addition of 100 mL of water. Theresulting solution was extracted with 3×150 mL of ethyl acetate, washedwith 2×100 mL of brine, dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. The residue was purified via columnchromatography on silica gel, eluting with ethyl acetate/petroleum ether(1:5). The collected fractions were concentrated to give 2-tert-butyl7-methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxylate(585 mg, 45%) as a white solid. MS: (ES, m/z): 384 [M+H]⁺.

Step-2:4-benzyl-7-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid

Into a 50-mL round-bottom flask was placed 2-tert-butyl 7-methyl4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2,7-dicarboxylate (585 mg, 1.53mmol), dichloromethane (5 mL) and trifluoroacetic acid (1 mL). Theresulting solution was stirred overnight at room temperature, and thenconcentrated under vacuum to give4-benzyl-7-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (510 mg) as a green solid which was used without any purification.MS: (ES, m/z): 328 [M+H]⁺.

Example 5—Intermediate 5:Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate-1,1-dioxide

Step-1:4-(tert-butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate

Di-tert-butyl dicarbonate (0.78 g, 3.6 mmol), triethylamine (0.50 mL,3.6 mmol), and 4-N,N-dimethylaminopyridine (0.44 g, 3.6, mmol) wereadded to a stirred solution ofmethyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (0.50 g, 2.4mmol) in 10 mL of acetonitrile. The reaction mixture was refluxed at 85°C. for 3 hours. The solvent was removed in vacuo, and the residue wasdissolved in 50 mL of ethyl acetate. The mixture was washed with 1 Maqueous HCl (2×25 mL) and brine (1×25 mL), dried over sodium sulfate,filtered, and concentrated in vacuo to afford4-(tert-butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate(780 mg, 95%) as an off-white solid, which was carried forward withoutfurther purification. MS (ESI-TOF) m/z: 331.9 [M+Na]⁺.

Step-2:4-(tert-butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate-1,1-dioxide

4-(tert-Butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate(712 mg, 2.30 mmol) was dissolved in dichloromethane (10 mL) and cooledto 0° C. in an ice bath. 3-Chloroperoxybenzoic acid (794 mg, 4.60 mmol)was added in one portion. The reaction mixture stirred at 0° C. for 1 h,was warmed to room temperature, and then stirred for 1 h. The solventwas removed in vacuo and 50 mL of ethyl acetate was added. Then themixture was washed with 10% aqueous potassium carbonate solution (2×25mL) and brine (1×25 mL). The organic phase was dried with sodium sulfateand then filtered. The solvent was removed in vacuo to afford4-(tert-butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate-1,1-dioxide(746 mg, 95%) as an off-white solid which was carried forward withoutfurther purification. MS (ESI-TOF) m/z: 363.9 [M+Na]⁺.

Step-3:Methyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate-1,1-dioxide

4-(tert-Butyl)-6-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4,6-dicarboxylate-1,1-dioxide(0.74 g, 2.2 mmol) was dissolved in dichloromethane (10 mL).Trifluoroacetic acid (2 mL) was added, and the reaction mixture stirredfor 2 h at room temperature. The reaction mixture was diluted withdichloromethane (25 mL) and washed with 10% aqueous potassium carbonatesolution (2×20 mL) and brine (1×20 mL). The organic phase was dried withsodium sulfate and filtered. The solvent was removed in vacuo to affordmethyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate-1,1-dioxide(0.50 g, 96%) as an off-white powder, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.63 (d, J=8.0 Hz, 1H), 7.41(d, J=1.5 Hz, 1H), 7.37 (bs, 1H), 7.17 (dd, J=8, 4 Hz, 1H), 3.84 (s,3H), 3.75 (m, 2H), 3.44 (m, 2H); MS (ESI-TOF) m/z: 242 [M+H]⁺.

Example 6—Intermediate 6:2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole

Sodium hydride (60% dispersion in mineral oil, 0.665 g, 16.63 mmol) wasadded to a solution of 2-bromo-1H-benzo[d]imidazole (2.73 g, 13.86 mmol)in DMF (30 mL), and the reaction stirred for 10 minutes at ambienttemperature. 1-Bromo-2-methoxyethane (1.541 ml, 16.63 mmol) was added,and reaction stirred overnight at ambient temperature. The reaction wasdiluted with ethyl acetate and washed several times with brine. Theorganic layer was separated and dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified via columnchromatography on a 100 gram silica gel column eluting with 20-40% ethylacetate-hexane. The desired fractions were combined and concentrated toafford 2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (2.9 g, 82%) asan orange oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.54-7.67 (m, 2H)7.14-7.34 (m, 2H) 4.42 (t, J=5.28 Hz, 2H) 3.67 (t, J=5.28 Hz, 2H) 3.20(s, 3H).

Example 7—Intermediate 7: methyl8-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Step 1: Methyl 3-fluoro-4-hydroxy-5-nitrobenzoate

Into a 500-mL 3-necked round-bottom flask, was placed methyl3-fluoro-4-hydroxybenzoate (4.27 g, 25.10 mmol, 1.00 equiv), ether (200mL). This was followed by the addition of nitric acid (65%) (3.48 mL,50.24 mmol, 2.00 equiv) dropwise with stirring at −10° C. To this wasadded fuming nitric acid (2.15 mL, 50.23 mmol, 2.00 equiv) dropwise withstirring at −10° C. The resulting solution was stirred for 2 h at roomtemperature (27° C.) and then slowly poured into 100 mL of water/ice.The mixture was extracted with 2×100 mL of dichloromethane, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:1)) to afford methyl3-fluoro-4-hydroxy-5-nitrobenzoate (4.3 g, 80% as a yellow solid. MS:(ESI, m/z): 214 [M−H]⁻.

Step 2: Methyl 3-amino-5-fluoro-4-hydroxybenzoate

Into a 250-mL round-bottom flask, was placed methyl3-fluoro-4-hydroxy-5-nitrobenzoate (4.3 g, 19.99 mmol, 1.00 equiv), MeOH(100 mL) and 10% Pd/C (430 mg). To the above hydrogen was introduced in.The resulting solution was stirred for 1 h at room temperature (25° C.).The solids were filtered out. The filtrate was concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with ethyl acetate/petroleum ether (1:3)) to afford methyl3-amino-5-fluoro-4-hydroxybenzoate (3.1 g, 84%) as a yellow solid. MS:(ESI, m/z): 186 [M+H]⁺.

Step 3: Methyl8-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 100-mL round-bottom flask, was placed methyl3-amino-5-fluoro-4-hydroxybenzoate (1 g, 5.40 mmol, 1.00 equiv),dichloromethane (40 mL) and TEA (2.25 mL, 16.21 mmol, 3.00 equiv). Thiswas followed by the addition of 2-chloroacetyl chloride (0.48 mL, 6.43mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solutionwas stirred for 2 hours at room temperature (25° C.) and additionalovernight at 60° C. The resulting mixture was cooled to room temperatureand then concentrated under vacuum. The crude product was washed with 5mL of dichloromethane to afford methyl8-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (980mg, 81%) as a yellow solid. MS: (ESI, m/z): 226 [M+H]⁺.

Example 8—Intermediate 8: methyl2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate

Step 1: Methyl 4-(hydroxymethyl)-3-nitrobenzoate

Into a 100-mL 3-necked round-bottom flask, was placed methyl4-formyl-3-nitrobenzoate (2.09 g, 9.99 mmol, 1.00 equiv), methanol (30mL). This was followed by the addition of NaBH₄ (760 mg, 20.09 mmol,2.01 equiv), in portions at 0° C. The resulting solution was stirred forovernight at room temperature (25° C.). The reaction was quenched by theaddition of 5 mL of water, and then concentrated under vacuum. Theresidue was diluted with 50 mL of water. The mixture was extracted with2×50 mL of dichloromethane, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with ethyl acetate/petroleum ether(1:1)) to afford methyl 4-(hydroxymethyl)-3-nitrobenzoate (1.28 g, 61%)as a yellow solid. ¹H-NMR: (DMSO 400 MHz, ppm): δ 8.51 (s, 1H), 8.32 (d,J=8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 5.76-5.74 (m, 1H), 4.91 (d, J=8 Hz,2H), 3.92 (s, 3H).

Step 2: Methyl 3-amino-4-(hydroxymethyl)benzoate

Into a 100-mL round-bottom flask, was placed methyl4-(hydroxymethyl)-3-nitrobenzoate (500 mg, 2.37 mmol, 1.00 equiv),methanol (20 mL), 10% Pd/C (300 mg). To the above hydrogen wasintroduced in. The resulting solution was stirred for 18 h at roomtemperature (25° C.). The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with ethyl acetate/petroleum ether(1:1)) to afford methyl 3-amino-4-(hydroxymethyl)benzoate (195 mg, 45%)as an off-white solid. MS: (ESI, m/z): 182 [M+H]⁺.

Step 3: Methyl 2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate

Into a 25-mL round-bottom flask, was placed methyl3-amino-4-(hydroxymethyl)benzoate (175 mg, 0.97 mmol, 1.00 equiv) intetrahydrofuran (10 mL). This was followed by the addition of a solutionof ditrichloromethyl carbonate (345 mg, 1.16 mmol, 1.20 equiv) intetrahydrofuran (1 mL) dropwise with stirring at 0° C. The resultingmixture was stirred for 10 minutes at 0° C. To this was added TEA (0.47mL, 3.38 mmol, 3.48 equiv) dropwise with stirring at 0° C. The resultingsolution was stirred for 3 h at room temperature (27° C.). The reactionmixture was then diluted with 50 mL of dichloromethane, washed with 2×30mL of water, dried over anhydrous magnesium sulfate and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with ethyl acetate/petroleum ether (1:3)) to affordmethyl 2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (190 mg,95%) as a off-white solid. MS: (ESI, m/z): 208 [M+H]⁺.

Example 9—Intermediate 9: methyl3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate)

Step 1: Methyl 4-(2-methylallyloxy)-3-nitrobenzoate

Into a 250-mL 3-necked round-bottom flask, was placed methyl4-hydroxy-3-nitrobenzoate (5 g, 25.36 mmol, 1.00 equiv), acetone (100mL), potassium carbonate (10.5 g, 75.97 mmol, 3.00 equiv), and3-bromo-2-methylprop-1-ene (3.79 mL, 37.04 mmol, 1.46 equiv). Theresulting solution was stirred for overnight at 50° C. and then cooledto room temperature. The solids were filtered out. The filtrate wasconcentrated under vacuum. The residue was diluted with 100 mL of water.The resulting solution was extracted with 2×100 mL of ethyl acetate,washed with 100 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with ethyl acetate/petroleum ether(1:4)) to afford methyl 4-(2-methylallyloxy)-3-nitrobenzoate (5 g, 78%)as a yellow solid. GCMS: (EI): 251 [M].

Step 2: Methyl 3-amino-4-(2-methylallyloxy)benzoate

Into a 250-mL 3-necked round-bottom flask, was placed methyl4-(2-methylallyloxy)-3-nitrobenzoate (2.51 g, 9.99 mmol, 1.00 equiv),ethanol (100 mL), water (30 mL) and NH₄Cl (1.59 g, 29.72 mmol, 3.00equiv). This was followed by the addition of Fe (5.6 g, 100.28 mmol,10.00 equiv) in portions at 60° C. The resulting solution was stirredfor 4 h at 90° C. and then cooled to 50° C. The solids were filteredout. The filtrate was concentrated under vacuum. The residue was dilutedwith 100 mL of water. The resulting solution was extracted with 2×50 mLof ethyl acetate, washed with 100 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedvia column chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:1)) to afford methyl3-amino-4-(2-methylallyloxy)benzoate (2.2 g, 100%) as a white solid. MS:(ESI, m/z): 222 [M+H]⁺.

Step 3: Methyl 3-azido-4-(2-methylallyloxy)benzoate

Into a 50-mL 3-necked round-bottom flask, was placed HCl (6M) (6 mL),methyl 3-amino-4-(2-methylallyloxy)benzoate (442 mg, 2.00 mmol, 1.00equiv). This was followed by the addition of a solution of NaNO₂ (166mg, 2.40 mmol, 1.20 equiv) in water (1 mL) dropwise with stirring at 0°C. The mixture was stirred for 20 min at 0° C. The pH value of thesolution was adjusted to 7 with sodium bicarbonate solid. To this wasadded a solution of NaN₃ (156 mg, 2.40 mmol, 1.20 equiv) in water (1 mL)dropwise with stirring at 0° C. The mixture was stirred for 30 min at 0°C. The solids were collected by filtration and dried to afford methyl3-azido-4-(2-methylallyloxy)benzoate (440 mg, 89%) as a yellow solid.MS: (ESI, m/z): 248 [M+H]⁺.

Step 4: Methyl1a-methyl-1a,2-dihydro-1H-azirino[1,2-d]benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl3-azido-4-(2-methylallyloxy)benzoate (440 mg, 1.78 mmol, 1.00 equiv),toluene (20 mL). The resulting solution was stirred for 4 h at 90° C.The reaction mixture was cooled to room temperature and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with ethyl acetate/petroleum ether (1:3)) to affordmethyl1a-methyl-1a,2-dihydro-1H-azirino[1,2-d]benzo[b][1,4]oxazine-6-carboxylate(280 mg, 65%) as yellow oil. MS: (ESI, m/z): 220 [M+H]⁺.

Step 5: Methyl3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl1a-methyl-1a,2-dihydro-1H-azirino[1,2-d]benzo[b][1,4]oxazine-6-carboxylate(280 mg, 1.28 mmol, 1.00 equiv), methanol (10 mL), 10% Pd/C (100 mg). Tothe above hydrogen was introduced in. The resulting solution was stirredfor overnight at room temperature (25° C.). The solids were filteredout, the filtrate was concentrated under vacuum to afford methyl3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (240 mg,85%) as colorless oil. MS: (ESI, m/z): 222 [M+H]⁺.

Example 10—Intermediate 10:3-((6-(methoxycarbonyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoicacid

Step-1: methyl4-(3-(tert-butoxycarbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

tert-butyl 3-(bromomethyl)benzoate (1.31 g, 4.83 mmol) was added to asolution of methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (1.00 g, 4.83mmol) and cesium carbonate (3.15 g, 9.65 mmol) in DMF (10 mL). Thereaction was stirred overnight at ambient temperature. The reaction wasdiluted with ethyl acetate (50 mL) and washed with 1N aq. NaOH (5 mL).The organic phase was separated, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by normal phase columnchromatography on silica gel (Biotage KP-SIL 50 g column, 15%-45%EtOAc/Hexanes gradient) to afford methyl4-(3-(tert-butoxycarbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(2.1 g, 5.28 mmol, 109%) as a white solid. MS: (ES, m/z): 398 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 9H) 2.73 (s, 2H) 2.81-2.92(m, 1H) 2.81-2.84 (m, 1H) 3.16 (s, 3H) 3.61-3.81 (m, 7H) 4.94 (s, 2H)5.27 (s, 3H) 7.13 (d, J=8.50 Hz, 2H) 7.32-7.50 (m, 4H) 7.51-7.79 (m, 2H)7.86 (d, J=8.21 Hz, 2H) 7.92-8.02 (m, 1H).

Step-2:3-((6-(methoxycarbonyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoicacid

methyl4-(3-(tert-butoxycarbonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(2.03 g, 5.11 mmol) was dissolved in CH₂Cl₂ (15 mL). Zinc (II) bromide(5.75 g, 25.2 mmol) was added. The resulting solution stirred for 16hours at ambient temperature. The reaction mixture was washed with H₂O(10 mL). The organic layer was separated, dried over Na₂SO₄, filteredand concentrated to afford3-((6-(methoxycarbonyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoicacid (3.5 mg, 0.009 mmol, 2.5%) as an off-white solid. MS: (ES, m/z):342 [M+H]⁺. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.76-3.85 (m, 4H)4.73-4.84 (m, 3H) 5.14-5.34 (m, 4H) 6.80-7.11 (m, 2H) 7.14-7.42 (m, 4H)7.51 (d, J=1.88 Hz, 1H) 7.57-7.90 (m, 2H) 7.91-7.98 (m, 2H).

Example11—N⁶-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamidehydrochloride (I-1)

Step-1: methyl4-methyl-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 10-mL round-bottom flask was placed6-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylicacid (150 mg, 0.60 mmol), THF (5 mL), triethylamine (182 mg, 1.80 mmol),oxan-4-amine (90 mg, 0.89 mmol), HOBT (122 mg, 0.90 mmol) and EDCI (288mg, 0.90 mmol). The resulting solution was stirred for 5 h at roomtemperature. The reaction was then quenched by the addition of 30 mL ofwater. The resulting solution was extracted with 3×30 mL of ethylacetate washed with 50 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified via columnchromatography on silica gel, eluting with ethyl acetate/petroleum ether(1:1). The collected fractions were concentrated to afford methyl4-methyl-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 50%) as a white solid. MS: (ES, m/z): 335 [M+H]⁺.

Step-2:N⁶-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamidehydrochloride

Into a 25-mL round-bottom flask was placed methyl4-methyl-2-[(oxan-4-yl)carbamoyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(100 mg, 0.30 mmol), methanol/THF (1:4, 3 mL), hydroxylamine (50% inwater, 1.15 g, 18 mmol), and aqueous sodium hydroxide solution (1 M, 0.6mL, 0.60 mmol). The resulting solution was stirred for 2 h at roomtemperature. The crude product (4 mL) was purified by Prep-HPLC with thefollowing conditions: Column: X Bridge C18, 19*150 mm, 5 μm; MobilePhase A: Water/0.05% FA, Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 5% B to 30% B in 7 min; 254 nm. 2 M HCl (0.2 mL, 0.60 mmol)was added to the collected fractions and the solution was lyophilized togiveN⁶-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamidehydrochloride (20.7 mg, 19%) as an off-white solid. ¹H NMR (DMSO-d₆, 300MHz): δ ppm 11.00 (s, 1H), 8.86-8.85 (d, J=1.5 Hz, 1H), 7.99-7.96 (d,J=7.8 Hz, 1H), 7.10-7.07 (t, J=4.8 Hz, 2H), 6.87-6.84 (d, J=8.4 Hz, 1H),4.73-4.69 (m, 1H), 3.83-3.80 (m, 3H), 3.44-3.30 (m, 3H), 3.30-3.16 (m,1H), 2.86 (s, 3H), 1.58-1.51 (m, 4H). MS: (ES, m/z): 336 [M+H]⁺.

The following compounds were prepared according to the proceduresdescribed above for Example 11.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-2

4-benzyl-N⁶-hydroxy- N²-(tetrahydro-2H- pyran-4-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 2,6-dicarboxamide (DMSO, 400 MHz, ppm): 10.94 (s,1H), 8.82 (s, 1H), 8.00-7.98 (d, J = 8 Hz, 1H), 7.36- 7.25 (m, 5H), 7.14(s, 1H), 7.06-7.04 (d, J = 8.4 Hz, 1H), 6.91-6.89 (d, J = 8.4 Hz, 1H),4.72- 4.69 (m, 1H), 4.58-4.46 (m, 2H), 3.81 (s, 3H), 3.52-3.49 (m, 1H),3.37- 3.34 (t, J = 19.2 Hz, 2H), 3.31 (s, 1H), 1.68-1.60 (t, J = 15.4Hz, 2H), 1.54-1.45 (m, 2H). 412 I-3

N-hydroxy-4-methyl- 2- (spiro[cyclopropane- l,3′-indoline]-1′-carbonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamidehydrochloride (DMSO, 400 MHz, ppm): 11.02 (s, 1H), 8.05-8.03 (d, J = 8Hz, 1H), 7.16-7.01 (m, 4H), 6.86-6.83 (t, J = 6.6 Hz, 2H), 5.14 (s, 1H),4.39- 4.27 (m, 2H), 3.53-3.41 (m, 2H), 2.91 (s, 3H), 1.15-1.06 (m, 4H)380 I-4

4-benzyl-N-hydroxy- 2- (spiro[cyclopropane- l,3′-indoline]-1′carbonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamidehydrochloride (DMSO, 400 MHz, ppm): 11.30 (s, 1H), 8.82 (br, 1H),8.05-8.04 (d, J = 7.6 Hz, 1H), 7.31- 7.21 (m, 6H), 7.18-7.11 (m, 2H),7.05-7.01 (t, J = 7.4 Hz, 2H), 6.94-6.84 (m, 2H), 5.14 (s, 1H),4.64-4.50 (m, 2H), 4.34- 4.32 (d, J = 10.4 Hz, 1H), 4.14-4.12 (d, J = 10Hz, 1H), 3.57-3.56 (d, J = 4.4 Hz, 2H), 1.16- 1.06 (m, 4H) 456 I-5

N²-benzyl-N⁶- hydroxy-4-methyl- 3,4-dihydro-2H- benzo[b][1,4]oxazine-2,6-dicarboxamide hydrochloride (DMSO, 300 MHz, ppm): 11.01 (s, 1H),8.60-8.57 (t, J = 6 Hz, 1H), 7.31-7.27 (t, J = 7.2 Hz, 2H), 7.24-7.19(m, 3H), 7.12-7.10 (t, J = 3.2 Hz, 2H), 6.87- 6.85 (d, J = 8 HZ, 1H),4.87-4.85 (t, J = 3.2 HZ, 1H), 4.38-4.28 (m, 2H), 3.44-3.40 (m, 1H),3.32- 3.29 (t, J = 5.6 Hz, 1H), 2.87 (s, 3H). 342 I-6

N^(2,4)-dibenzyl-N⁶- hydroxy-3,4-dihydro- 2H- benzo[b][1,4]oxazine-2,6-dicarboxamide (DMSO, 300 MHz, ppm): 10.96 (s, 1H), 8.63-8.60 (t, J =6.2 Hz, 1H), 7.34-7.16 (m, 11H), 7.09-7.04 (m, 1H), 6.91-6.89 (d, J =8.4 Hz, 1H), 4.85-4.83 (m, 1H), 4.52 (s, 2H), 4.40-4.28 (m, 2H), 3.55-3.51 (m, 1H), 3.52-3.40 (m, 1H) 418

Example12—N⁷-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide(I-7)

Step-1: methyl4-methyl-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate

Into a 10-mL vial was placed7-(methoxycarbonyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylicacid (100 mg, 0.40 mmol), THF (2 mL), EDCI (192 mg, 0.60 mmol), HOBT (81mg, 0.60 mmol), triethylamine (121 mg, 1.20 mmol) and oxan-4-amine (60mg, 0.59 mmol). The resulting mixture was stirred overnight at roomtemperature. The reaction was then quenched by the addition of 30 mL ofwater. The resulting solution was extracted with 3×50 mL of ethylacetate, washed with 2×30 mL of brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified via column chromatography on silica gel, eluting with ethylacetate/petroleum ether (1:5). The collected fractions were concentratedto give methyl4-methyl-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate(103 mg, 77%) as a brown solid. MS: (ES, m/z): 335 [M+H]⁺.

Step-2:N⁷-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide

Into a 25-mL round-bottom flask was placed methyl4-methyl-2-(tetrahydro-2H-pyran-4-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate(103 mg, 0.31 mmol), methanol/THF (1:4, 2 mL), hydroxylamine (50% inwater, 0.62 mL, 18.6 mmol), and aqueous sodium hydroxide solution (1 M,0.62 mL, 0.62 mmol). The resulting solution was stirred for 4 h at roomtemperature. The crude product was purified by Prep-HPLC with thefollowing conditions (Waters III): Column, Sunfire C18 19*150 mm; mobilephase, water with 0.05% FA and CH₃CN (5% up to 40% in 9 min); Detector,UV 220 & 254 nm. The collected fractions was lyophilized to giveN⁷-hydroxy-4-methyl-N²-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,7-dicarboxamide(42.5 mg, 41%) as a pink solid. ¹H NMR (DMSO, 400 MHz) δ ppm: 10.89 (s,1H), 8.78 (s, 1H), 8.00-7.98 (d, J=8.0 Hz, 1H), 7.31-7.28 (m, 2H),6.72-6.70 (d, J=8.0 Hz, 1H), 4.67-4.64 (m, 1H), 3.89-3.80 (m, 3H),3.50-3.46 (m, 1H), 3.37-3.31 (m, 2H), 3.27-3.22 (m, 1H), 2.89 (s, 3H),1.69-1.45 (m, 4H). MS: (ES, m/z): 358 [M+23]⁺.

The following compounds were prepared according to the proceduresdescribed above for Example 12.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-8

4-benzyl-N⁷-hydroxy- N²-(tetrahydro-2H- pyran-4-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 2,7-dicarboxamide (DMSO, 400 MHz, ppm): 10.86 (s,1H), 8.77 (s, 1H), 8.02-8.00 (d, J = 8.0 Hz, 1H), 7.35- 7.18 (m, 7H),6.68- 6.66 (d, J = 8.4 Hz, 1H), 4.69-4.66 (m, 1H), 4.62-4.50 (m, 2H),3.87-3.79 (m, 3H), 3.62-3.58 (m, 1H), 3.45-3.40 (m, 2H), 3.37-3.33 (m,1H), 1.68-1.47 (m, [M + H]⁺ 434 4H) I-9

N-hydroxy-4-methyl- 2- (spiro[cyclopropane- 1,3′-indoline]-1′-carbonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine- 7-carboxamide (DMSO,400 MHz, ppm): 10.89 (s, 1H), 8.77 (s, 1H), 8.06-8.03 (d, J = 8.8 Hz,1H), 7.33- 7.30 (m, 1H), 7.23 (s, 1H), 7.17- 7.13 (t, J = 7.4 Hz, 1H),7.05-7.02 (m, 1H), 6.87-6.85 (d, J = 7.6 Hz, 1H), 6.74- 6.72 (d, J = 8.4Hz, 1H), 5.07 (s, 1H), 4.40-4.38 (d, J = 10.0 Hz, 1H), 4.31- 4.28 (d, J= 10.8 Hz, 1H), 3.57-3.48 (m, 2H), 2.95 (s, 3H), 1.16-1.09 (m, 2H),1.07-1.00 (m, 2H) 380 I-10

4-benzyl-N-hydroxy- 2- (spiro[cyclopropane- 1,3′-indoline]-1′-carbonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine- 7-carboxamide (DMSO,400 MHz, ppm): 10.86 (s, 1H), 8.78 (s, 1H), 8.06-8.04 (d, J = 7.6 Hz,1H), 7.30- 7.22 (m, 7H), 7.18- 7.14 (m, 1H), 7.06- 7.02 (t, J = 7.4 Hz,1H), 6.87-6.85 (d, J = 6.8 Hz, 1H), 6.71- 6.68 (d, J = 8.8 Hz, 1H),5.10-5.09 (d, J = 4.8 Hz, 1H), 4.68- 4.64 (d, J = 16.0 Hz, 1H),4.58-4.54 (d, J = 16.4 Hz, 1H), 4.38-4.35 (d, J = 10.8 Hz, 1H), 4.22-4.19 (d, J = 10.4 Hz, 1H), 3.66-3.65 (d, J = 4.4 Hz, 2H), 1.15- 1.05 (m,4H) 456 I-11

N²-benzyl-N⁷- hydroxy-4-methyl- 3,4-dihydro-2H- benzo[b][1,4]oxazine-2,7-dicarboxamide (DMSO, 400 MHz, ppm): 10.90 (s, 1H), 8.77 (s, 1H),8.62-8.59 (t, J = 6.0 Hz, 1H), 7.31- 7.27 (t, J = 8.4 Hz, 4H), 7.23-7.18(m, 3H), 6.73-6.71 (d, J = 8.4 Hz, 1H), 4.82- 4.80 (m, 1H), 4.39- 4.27(m, 2H), 3.49- 3.46 (m, 1H), 3.38- 3.33 (m, 1H), 2.90 (s, 3H) 342 I-12

N^(2,4)-dibenzyl-N⁷- hydroxy-3,4-dihydro- 2H- benzo[b][1,4]oxazine-2,7-dicarboxamide (DMSO, 400 MHz, ppm): 10.89 (s, 1H), 8.76 (s, 1H),8.64 (s, 1H), 7.34- 7.20 (m, 8H), 7.19- 7.17 (m, 4H), 6.68- 6.66 (d, J =8.8 Hz, 1H), 4.83-4.81 (m, 1H), 4.55 (s, 2H), 4.37-4.30 (m, 2H),3.63-3.60 (t, J = 6.2 Hz, 1H), 3.53- 3.48 (m, 1H) 417

Example13—N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxamide(I-13)

Step-1: Methyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate

A 10-mL microwave vial was equipped with stir bar and2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (0.050 g, 0.196 mmol),methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate (0.075 g, 0.392 mmol),and concentrated HCl (0.0060 mL, 0.20 mmol) were combined in 2-propanol(2 mL). The resulting mixture was heated to 150° C. in the microwave for2 hours. The reaction mixture was concentrated under vacuum to affordmethyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(0.0152 g, 22%) as a yellow oil. MS (ESI, m/z): 366 [M+H]⁺.

Step-2:N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxamide

Methyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate(0.0152 g, 0.041 mmol) was dissolved in tetrahydrofuran (1 mL) andmethanol (0.25 mL). Hydroxylamine (0.112 g, 1.195 mmol, 50% in water),and aqueous sodium hydroxide solution (1 M, 0.239 mL) were added. Theresulting solution stirred for 2 hours at room temperature. The crudeproduct was purified by Prep-HPLC with the following conditions: ColumnWaters RP-HPLC XBridge Prep C18 5 uM OBD 19×50 mm; Mobile Phase A:Water/0.05% Formic Acid, Mobile Phase B: ACN/0.05% Formic Acid B: ACN;Flow rate: 23 mL/min; Gradient: 25% B to 65% B in 6.6 min, hold 0.9 min;220 nm and 254 nm. The collected fractions were dried under vacuum toaffordN-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxamide(0.0025 g, 17%). MS (ESI, m/z): 367 [M+H]⁺.

Example14—1-(1H-1,3-benzodiazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-5-carboxamide(I-14)

1-(1H-1,3-benzodiazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-5-carboxamidewas synthesized according to the procedures outlined above forN-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxamide(I-13; Example 13). MS (ESI, m/z): 309 [M+H]⁺.

Example15—N-hydroxy-4-(3-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide(I-15)

A 2 mL vial was chargedmethyl-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate-1,1-dioxide(0.2 M in acetonitrile, 150 μL, 30 μmol) and cesium carbonate (39 mg,120 μmol). A solution of1-(bromomethyl)-3-((trifluoromethyl)sulfonyl)benzene (0.2 M inacetonitrile, 300 μL, 60 mmol) was added, and the vial was sealed andshaken at 50° C. for 72 h. The solvent was removed under a stream ofnitrogen. The residue was diluted with brine (500 μL) and extracted withethyl acetate (2×500 μL). The combined organic layers were dried under astream of nitrogen, and a solution of THF/methanol (3:1, 200 μL) wasadded to the residue. The vial was sealed and shaken at 50° C. for 15minutes to dissolve the residue, then cooled to room temperature.Hydroxylamine (150 μL, 50% v/v solution in water) was added, followed by1 N aqueous sodium hydroxide solution (100 μL). The mixture was sealedand then shaken at room temperature for 18 h. The reaction mixture wasconcentrated under a stream of nitrogen at room temperature, thendissolved in 500 μL of DMSO and purified by mass triggered preparativeHPLC (Column: Waters Sunfire C18, 5 μm, 19×50 mm; Mobile Phase: water(0.1% formic acid) and acetonitrile (0.1% formic acid) (15% to 100%acetonitrile in 6 min; flow rate: 23 mL/min); Detector: UV 254/220 nm).The product-containing fractions were combined and concentrated in aGenevac to affordN-hydroxy-4-(3-((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide-1,1-dioxide(3.5 mg, 25% yield). (ESI, m/z) 464.03 [M]⁺.

The following compounds were synthesized according to the procedureoutlined above for Example 15.

HPLC Compd. LC-MS RT No. Structure IUPAC Name [M + H]⁺ (min) I-16

N-hydroxy-4-(1-(4- (methylsulfonyl)phenyl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine- 6-carboxamide-1,1-dioxide 425 1.05I-17

N-hydroxy-3-oxo-4-(4- ((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 431 1.13 I-18

N-hydroxy-3-oxo-4-(3- ((trifluoromethyl)sulfonyl)benzyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 431 1.11

Example16—N-hydroxy-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-19)

A half-dram vial was charged with methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (0.2 M inN,N-dimethylacetamide, 150 μL, 30 μmol) and potassium carbonate (20.7mg, 150 μmol). Then a solution of1-(bromomethyl)-4-(trifluoromethoxy)benzene (0.2 M inN,N-dimethylacetamide, 400 μL, 80 μmol) was added. The system was sealedand shaken at 50° C. for 16 h, and then the solvent was removed under astream of nitrogen. The residue was diluted with ethyl acetate (0.6 mL)and brine (0.5 mL), and the mixture was shaken. The organic layer wasseparated, and the aqueous phase was extracted with ethyl acetate (0.6mL). The combined organic layers were dried under a stream of nitrogen.THF/methanol (3:1, 200 μL) was added to the residue. The vial was sealedand shaken at 50° C. for 15 min to dissolve the residue, then cooled toroom temperature. Hydroxylamine (150 μL, 50% v/v solution in water) wasadded, followed by 1 N aqueous sodium hydroxide solution (100 μL). Themixture was sealed and then shaken at room temperature for 16 h. Thereaction mixture was concentrated under a stream of nitrogen at roomtemperature, then dissolved in 500 μL of DMSO, and purified by masstriggered preparative HPLC (Column: Waters Sunfire C18, 5 μm, 19×50 mm;Mobile Phase: water (0.1% formic acid) and acetonitrile (0.1% formicacid) (15% to 100% acetonitrile in 6 min; flow rate: 23 mL/min);Detector: UV 254/220 nm). The product-containing fractions were combinedand concentrated in a Genevac to affordN-hydroxy-4-(4-(trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(6.7 mg, 60.6%). (ES, m/z) 369 [M+H]⁺, LC-MS R_(t) 1.35 min.

The following compounds were synthesized according to the above protocolof Example 16.

HPLC Compd. LC-MS RT No. Structure IUPAC Name [M + H]⁺ (min) I-20

4-((2-cyclopropylthiazol- 4-yl)methyl)-N-hydroxy- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 332 1.00 I-21

N-hydroxy-4- (imidazo[2,1-b]thiazol-6- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 331 0.63 I-22

N-hydroxy-4-(2- methylallyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine-6-carboxamide 249 0.98 I-23

4-(2,6-dichlorobenzyl)-N- hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 353 1.27 I-24

4-(3-fluorobenzyl)-N- hydroxy-3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 303 1.11 I-25

N-hydroxy-4-(2- (trifluoromethoxy)benzyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 369 1.31 I-26

N-hydroxy-4-(2- morpholino-2-oxoethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 322 0.58 I-27

4-(2-fluorobenzyl)-N- hydroxy-3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 303 1.11 I-28

N-hydroxy-4-((1- isopropyl-1H- benzo[d]imidazol-2-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide 367 0.79I-29

N-hydroxy-4-((1-(2- methoxyethyl)-1H- benzo[d]imidazol-2-yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide 383 0.72I-30

4-((1- (cyclopropylmethyl)-1H- benzo[d]imidazol-2- yl)methyl)-N-hydroxy-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 379 0.84

Example17—4-(cyclobutylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-31)

A half-dram vial was charged with methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (0.2 M inN,N-dimethylacetamide, 150 μL, 30 μmol) and sodium hydride (1.8 mg, 60%in mineral oil, 45 μmol), and the mixture was shaken for 10 minutes. Asolution of (bromomethyl)cyclobutane (0.4 M in N,N-dimethylacetamide,150 μL, 60 μmol) was added, and the system was sealed and shaken at roomtemperature for 16 h. The solvent was removed under a stream ofnitrogen. The residue was diluted with ethyl acetate (0.6 mL) and brine(0.5 mL), and the mixture was shaken. The organic layer was separatedand the aqueous phase was extracted with ethyl acetate (0.6 mL). Thecombined organic layers were dried under a stream of nitrogen.THF/methanol (3:1, 200 μL) was added to the residue. The vial was sealedand shaken at 50° C. for 15 minutes to dissolve the residue, then cooledto room temperature. Hydroxylamine (150 μL, 50% v/v solution in water)was added, followed by 1 N aqueous sodium hydroxide solution (100 μL).The mixture was sealed and then shaken at room temperature for 16 h. Thereaction mixture was concentrated under a stream of nitrogen at roomtemperature, then dissolved in 500 μL of DMSO and purified by masstriggered preparative HPLC (Column: Waters Sunfire C18, 5 μm, 19×50 mm;Mobile Phase: water (0.1% formic acid) and acetonitrile (0.1% formicacid) (15% to 100% acetonitrile in 6 min; flow rate: 23 mL/min);Detector: UV 254/220 nm). The product-containing fractions were combinedand concentrated in a Genevac to afford4-(cyclobutylmethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(1.0 mg, 12%). (ES, m/z) 277 [M+H]⁺, LC-MS R_(t) 0.86 min.

The following compounds were synthesized according to the above protocolof Example 17.

LC- MS HPLC Compd. [M + RT No. Structure IUPAC Name H]⁺ (min) I-32

4-benzyl-N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4 ]oxazine-6-carboxamide 2.99 0.87 I-33

4-(3-fluorobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 317 0.91 I-34

4-(4-chlorophenethyl)-N- hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 347 1.10 I-35

N-hydroxy-3-oxo-4-(4- (trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 367 1.12 I-36

N-hydroxy-3-oxo-4-(4- (trifluoromethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 383 1.16 I-37

4-(4-fluorobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 317 0.92 I-38

N-hydroxy-4-(4- methylbenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 313 0.98 I-39

N-hydroxy-3-oxo-4-propyl-3,4- dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 251 0.69 I-40

N-hydroxy-3-oxo-4- (prop-2-yn-1- yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 247 0.61 I-41

4-allyl-N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide 249 0.63 I-42

4-cyclopentyl-N-hydroxy- 3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 277 0.85 I-43

N-hydroxy-4-(2-methoxyethyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 267 0.57 I-44

N-hydroxy-4-(4- methylpent-3-en- 1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 291 0.96 I-45

4-butyl-N-hydroxy-3- oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 265 0.82 I-46

4-(sec-butyl)-N-hydroxy- 3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 265 0.79 I-47

N-hydroxy-4-((1- methylpiperidin- 2-yl)methyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 320 0.44 I-48

N-hydroxy-3-oxo-4- ((tetrahydro- 2H-pyran-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4 ]oxazine- 6-carboxamide 307 0.64 I-49

4-((1,1-dioxidotetrahydro-2H- thiopyran-4-yl)methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3550.58 I-50

4-(2-(cyclopropylmethoxy) ethyl)- N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 307 0.79 I-51

4-(2-(cyclopropyl(methyl) amino)- 2-oxoethyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 320 0.62 I-52

4-(2-(1,1- dioxidoisothiazolidin-2- yl)ethyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4 ]oxazine- 6-carboxamide 356 0.56 I-53

N-hydroxy-3-oxo-4- (2-(2,2,2- trifluoroethoxy)ethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 335 0.81 I-54

4-(2-(1,1- dioxidotetrahydrothiophen- 3- yl)ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4 ]oxazine- 6-carboxamide 355 0.61 I-55

N-hydroxy-3-oxo-4-(2-(4- (trifluoromethyl)phenoxy) ethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 397 1.20 I-56

4-(2-(4-(N,N- dimethylsulfamoyl)phenoxy) ethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 436 0.91 I-57

N-hydroxy-4-isobutyl-3- oxo-3,4- dihydro-2H-benzo[b][1,4 ]oxazine-6-carboxamide 265 0.80 I-58

N-hydroxy-3-oxo-4- phenethyl-3,4- dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 313 0.94 I-59

N-hydroxy-4-isopentyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide 279 0.93 I-60

N-hydroxy-4-(3- methoxybenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 329 0.89 I-61

N-hydroxy-3-oxo-4- (pyridin-2- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 300 0.60 I-62

4-(benzo[c][1,2,5] oxadiazol-5- ylmethyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 341 0.88 I-63

N-hydroxy-4- (2-methoxybenzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 329 0.92 I-64

4-(4-chlorobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 333 1.02 I-65

N-hydroxy-3-oxo-4-(2- (trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 367 1.06 I-66

N-hydroxy-3-oxo-4-(2- (trifluoromethoxy)benzyl)- 3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 383 1.10 I-67

N-hydroxy-3-oxo-4-(1- phenylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 313 0.93 I-68

N-hydroxy-4-(3- methylbenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 313 0.97 I-69

4-(2-fluorobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 317 0.89 I-70

4-(4-(tert-butyl)benzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 355 1.27 I-71

4-(3,4-difluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 335 0.97 I-72

N-hydroxy-4-(2-methyl-5- (trifluoromethyl)benzyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 380 1.14 I-73

4-(2-fluoro-5- (trifluoromethyl)benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.10 I-74

4-(2-fluoro-3- methylbenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 331 1.00 I-75

4-([1,1′-biphenyl]-3- ylmethyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 375 1.22 I-76

N-hydroxy-4-((4- methyl-2- phenylthiazol-5-yl)methyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 396 1.08 I-77

N-hydroxy-3-oxo-4- [(1-phenyl- 1H-1,2,3-triazol-4- yl)methyl]-3,4-dihydro-2H-1,4- benzoxazine-6- carboxamide 366 0.88 I-214

N-hydroxy-3-oxo-4- (pyridin-3- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 300 0.31 I-215

N-hydroxy-3-oxo-4-(pyridin-4- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 300 0.29 I-216

N-hydroxy-4-(imidazo[1,2- a]pyridin-2-ylmethyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 339 0.31 I-217

4-((5-fluorobenzo[d]oxazol-2- yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide 358 0.96 I-218

4-((6-fluorobenzo[d] oxazol-2- yl)methyl)-N-hydroxy-3 -oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 358 0.93 I-219

4-(3,4-dimethylbenzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 327 1.11 I-220

N-hydroxy-3-oxo-4-(3- phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 391 1.26 I-221

N-hydroxy-4-(4-(oxazol-2- yl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 366 0.91 I-222

N-hydroxy-3-oxo-4- ((1-phenyl- 1H-pyrazol-3-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 365 1.01 I-223

N-hydroxy-3-oxo-4- ((1-phenyl- 1H-pyrazol-4-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 365 0.97 I-224

4-(4-(1H-pyrazol-1-yl)benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 365 0.92 I-225

N-hydroxy-2,2-dimethyl- 3-oxo-4- (3-phenoxybenzyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 419 1.43 I-226

4-(3-(4-chlorophenoxy) benzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 425 1.40 I-227

4-(3-(4-chlorophenoxy) benzyl)-N- hydroxy-2,2-dimethyl- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 453 1.57 I-228

N-hydroxy-3-oxo-4-(2- phenoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 391 1.25 I-229

N-hydroxy-3-oxo-4-(4- phenoxybenzyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 391 1.27 I-230

N-hydroxy-4- (naphthalen-1- ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 349 1.11 I-231

N-hydroxy-3-oxo-4- (quinolin-6- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.48 I-232

N-hydroxy-3-oxo-4- (quinolin-2- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.87 I-233

N-hydroxy-3-oxo-4-((6- (trifluoromethyl)benzo [d]oxazol-2-yl)methyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4081.13 I-234

N-hydroxy-3-oxo-4-((5- (trifluoromethyl)benzo[d] oxazol-2-yl)methyl)-3,4-dihydro- 2H- benzo[b][1,4]oxazine-6- carboxamide 4081.12 I-235

4-(2-cyanobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 324 0.85 I-236

4-(3-cyanobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 324 0.86 I-237

4-(4-cyanobenzyl)-N- hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 324 0.87 I-238

N-hydroxy-4-((2-methyl- 2H- indazol-5-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 353 .074 I-239

N-hydroxy-4-((2- methylbenzo[d]oxazol-6- yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 354 0.82 I-240

N-hydroxy-4-((2- methyl-2H- indazol-6-yl)methyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 353 0.77 I-241

N-hydroxy-1-(4-methoxybenzyl)- 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide 330 0.79 I-242

4-(2-chloro-4- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 363 1.06 I-243

4-(3-chloro-4- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 363 1.04 I-244

N-hydroxy-4-(4- methoxy-3- methylbenzyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide 343 1.05 I-245

4-(3-fluoro-4- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 347 0.97 I-246

N-hydroxy-4-(4- methoxy-3- (trifluoromethyl)benzyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 397 1.15 I-247

4-(2,3-difluoro-4- methoxybenzyl)- N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 365 1.02 I-248

4-(2,6-difluoro-4- methoxybenzyl)- N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 365 1.00 I-249

N-hydroxy-4-(4- methoxy-2- (trifluoromethyl)benzyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 397 1.16 I-250

4-(4-ethoxy-3,5- difluorobenzyl)- N-hydroxy-3-oxo-3,4 -dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 379 1.14 I-251

4-([1,1′-biphenyl]-4- ylmethyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 375 1.27 I-252

4-(2,5-dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.13 I-253

4-(2,6-dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.04 I-254

4-(2,3-dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.15 I-255

4-((5-chloro-2- phenylthiazol-4- yl)methyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 416 1.27 I-256

4-(2,4-dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.17 I-257

4-([1,1′-biphenyl]-2- ylmethyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 375 1.23 I-258

4-(3,4-dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.18 I-259

4-(2-chloro-5- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 401 1.21 I-260

4-((6-chloro-1- (cyclopropylmethyl)-1H- benzo[d]imidazol-2-yl)methyl)-N- hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide 427 1.13 I-261

4-((5-chloro-6- methylbenzo[d]oxazol-2- yl)methyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 388 1.13 I-262

N-hydroxy-3-oxo-4-(2- ((trifluoromethyl)thio) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 399 1.22 I-263

N-hydroxy-3-oxo-4-(3- ((trifluoromethyl)thio)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide 399 1.25 I-264

N-hydroxy-3-oxo-4-(4- ((trifluoromethyl)thio) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 399 1.28 I-265

4-(2-fluoro-3- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.16 I-266

4-(3-fluoro-4- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.19 I-267

4-(4-fluoro-3- (trifluoromethyl)benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.17 I-268

4-(5-fluoro-2- (trifluoromethyl)benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.14 I-269

4-((6-chloro-1-ethyl-1H- benzo[d]imidazol-2-yl) methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4011.02 I-270

4-(2-chloro-4- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.06 I-271

N-hydroxy-3-oxo-4-((2- phenylthiazol-4-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 382 1.13 I-272

4-((5-chlorobenzo[d] oxazol-2- yl)methyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 374 1.04 I-273

4-(2-chloro-6- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 0.98 I-274

4-(2-fluoro-4- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.18 I-275

4-(2-fluoro-6- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.07 I-276

4-(3-fluoro-5- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.19 I-277

4-(4-fluoro-2- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 385 1.15 I-278

4-((6-chloro-1-methyl-1H- benzo[d]imidazol-2-yl) methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3870.91 I-279

4-((1-(cyclopropylmethyl)- 1H- benzo[d]imidazol-2-yl) methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3930.79 I-280

4-(2,4-dimethylbenzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 327 1.10 I-281

N-hydroxy-4-((1- isopropyl-1H- benzo[d]imidazol-2-yl) methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 381 0.71 I-282

N-hydroxy-3-oxo-4- ((1-propyl- 1H-benzo[d]imidazol-2-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 381 0.77I-283

N-hydroxy-4-((2-methyl-4- propylthiazol-5-yl) methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 362 0.86 I-284

4-((3-benzyl-3H- imidazo[4,5- b]pyridin-2-yl)methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4300.98 I-285

N-hydroxy-4-((5- methoxybenzo[d]oxazol-2- yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 370 0.96 I-286

N-hydroxy-4-((5- methylbenzo[d]oxazol-2- yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 354 1.03 I-287

4-((6-chlorobenzo[d] oxazol-2- yl)methyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 374 1.04 I-288

4-(benzo[d]oxazol-2-ylmethyl)-N- hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 340 0.88 I-289

4-(benzo[d]thiazol-2- ylmethyl)-N- hydroxy-3-oxo-3,4 -dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 356 1.51 I-290

4-((5-chlorobenzo[d] thiazol-2- yl)methyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 390 1.13 I-291

4-((6-fluorobenzo[d] oxazol-2- yl)methyl)-N- hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3861.14 I-292

N-hydroxy-2,2- dimethyl-4-((6- methylbenzo[d]oxazol-2-yl)methyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide382 1.20 I-293

N-hydroxy-4- (imidazo[1,2- a]pyridin-2-ylmethyl)-2,2-dimethyl-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3670.51 I-294

4-((6-chlorobenzo[d] oxazol-2- yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4021.25 I-295

4-(benzo[d]thiazol-2- ylmethyl)-N- hydroxy-2,2-dimethyl- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 384 1.19 I-296

4-((5-chlorobenzo[d] thiazol-2- yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4181.33 I-297

N-hydroxy-2,2-dimethyl- 3-oxo-4- phenethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 341 1.18 I-298

N-hydroxy-2,2-dimethyl- 3-oxo-4- (3-phenylpropyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 355 1.29 I-299

4-(2,6-dichlorobenzyl)- N-hydroxy- 2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide 395 1.22 I-300

N-hydroxy-2,2-dimethyl- 3-oxo-4- (3-(trifluoromethyl) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 395 1.32 I-301

4-(4-chlorophenethyl)-N- hydroxy- 2,2-dimethyl-3-oxo-3,4 -dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide 375 1.31 I-302

N-hydroxy-2,2-dimethyl- 3-oxo-4- (2-(trifluoromethoxy) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 411 1.33 I-303

(S)-N-hydroxy-2,2-dimethyl-3- oxo-4-(1-phenylethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 341 1.17 I-304

4-(cyclohexylmethyl)- N-hydroxy- 2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 333 1.30 I-305

N-hydroxy-2,2-dimethyl- 3-oxo-4- (4-(trifluoromethyl) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 395 1.34 I-306

4-([1,1′-biphenyl]-4- ylmethyl)-N- hydroxy-2,2-dimethyl- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 403 1.45 I-307

N-hydroxy-2,2-dimethyl- 3-oxo-4- ((2-phenylthiazol-4-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 410 1.31 I-308

4-((5-chloro-2-phenylthiazol-4- yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 4441.47 I-309

4-((5-benzyl-2- phenylthiazol-4- yl)methyl)-N-hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 5001.71 I-310

N-hydroxy-2,2-dimethyl- 3-oxo-4- (4-(trifluoromethoxy) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 411 1.37 I-311

4-([1,1′-biphenyl]-3- ylmethyl)-N- hydroxy-2,2-dimethyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 403 1.44 I-312

4-(3,4-dichlorobenzyl)- N-hydroxy- 2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 395 1.38 I-313

4-(4-(tert-butyl)benzyl)-N- hydroxy-2,2-dimethyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 383 1.49 I-314

4-(4-(benzyloxy)benzyl)-N- hydroxy-2,2-dimethyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 433 1.46 I-315

4-([1,1′-biphenyl]-2- ylmethyl)-N- hydroxy-2,2-dimethyl- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 403 1.41 I-316

4-(3,4-dimethylbenzyl)-N- hydroxy-2,2-dimethyl-3- oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 355 1.29 I-317

N-hydroxy-2,2-dimethyl-4- (naphthalen-2-ylmethyl)- 3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 377 1.32 I-318

4-cinnamyl-N-hydroxy-2,2- dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 353 1.25 I-319

N-hydroxy-2,2-dimethyl- 3-oxo-4- (3-(trifluoromethoxy) benzyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 411 1.35 I-320

N-hydroxy-2,2-dimethyl- 3-oxo-4- ((5-phenylisoxazol-3- yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 394 1.27 I-321

4-(2-fluoro-4- (trifluoromethyl) benzyl)-N- hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 413 1.37I-322

4-(2-fluoro-4- (trifluoromethoxy) benzyl)-N- hydroxy-2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 429 1.40I-323

N-hydroxy-4- (naphthalen-2- ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 349 1.12 I-324

4-((1H-pyrrolo[2,3- b]pyridin-5- yl)methyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 339 0.61 I-325

4-((1,3-dimethyl-1H- pyrazolo[3,4- b]pyridin-5-yl)methyl)- N-hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 368 0.77 I-326

N-hydroxy-3-oxo-4- ((2-oxo-1,2- dihydroquinolin-3-yl) methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 366 0.81 I-327

N-hydroxy-4-((6- methyl-4-oxo- 4H-pyrido[1,2-a] pyrimidin-2-yl)methyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide381 0.71 I-328

N-hydroxy-3-oxo-4-((7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 3560.51 I-329

N-hydroxy-3-oxo-4- ((7-oxo-4,7- dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)methyl)-3,4- dihydro-2H-benzo[b][1,4] oxazine-6-carboxamide 357 0.50 I-330

N-hydroxy-4-(4- isopropoxybenzyl)-3- oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide 357 1.12 I-331

4-(4- cyclobutoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 369 1.19 I-332

N-hydroxy-4-((6- methoxypyridin- 3-yl)methyl)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 330 .078 I-333

N-hydroxy-3-oxo-4- (quinoIin-3- ylmethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.65 I-334

N-hydroxy-4- (isoquinolin-3- ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.78 I-335

N-hydroxy-3-oxo-4- (quinolin- ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.51 I-336

N-hydroxy-4- (isoquinolin-6- ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.39 I-337

N-hydroxy-4 -(isoquinolin-7- ylmethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 350 0.43 I-338

N-hydroxy-4- (imidazo[1,2- a]pyridin-7-ylmethyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazine- 6-carboxamide 339 0.30 I-339

N-hydroxy-3-oxo-4- (pyrazolo[1,5- a]pyridin-5-ylmethyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 339 0.77 I-340

4-(3-chloro-2- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.08 I-341

4-(2-fluoro-4- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 347 0.98 I-342

4-(3-fluoro-5- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 347 1.02 I-343

4-(3-chloro-5- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.10 I-344

4-(4-chloro-2- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.10 I-345

4-(4-chloro-3- (trifluorornethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 401 1.25 I-346

4-(4-chloro-3- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.11 I-347

4-(2-chloro-5- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 363 1.06 I-348

4-(5-chloro-2- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.07 I-349

4-(3-chloro-5- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 401 1.27 I-350

4-(4-chloro-3- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 363 1.08 I-351

4-(3-chloro-4- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.09 I-352

4-(2-chloro-5- fluorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 351 1.05 I-353

4-(4-fluoro-3- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 347 0.97 I-354

4-(2-chloro-3- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 401 1.23 I-355

4-(3,5- dichlorobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 367 1.20 I-356

4-(2-chloro-4- (trifluoromethyl) benzyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide 401 1.25

Example18—N-hydroxy-4-pentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-78)

A half-dram vial was charged with methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (0.2 M inN,N-dimethylacetamide, 150 μL, 30 μmol) and pentanal (0.2M in1,2-dichloroethane, 300 μL, 60 μmol). A solution of sodiumtriacetoxyborohydride (0.2 M in 1,2-dichloroethane, 450 μL, 90 μmol) wasadded, and the system was sealed and shaken at room temperature for 16h. The solvent was removed under a stream of nitrogen, the residue wasdiluted with ethyl acetate (0.6 mL) and a solution of 1 N sodiumhydroxide in brine (0.5 mL), and the mixture was shaken. The organiclayer was separated and the aqueous phase was extracted with ethylacetate (0.6 mL). The combined organic layers were dried under a streamof nitrogen. THF/methanol (3:1, 200 μL) was added to the residue. Thevial was sealed and shaken at 50° C. for 15 minutes to dissolve theresidue, then cooled to room temperature. Hydroxylamine (150 μL, 50% v/vsolution in water) was added, followed by 1 N aqueous sodium hydroxidesolution (100 μL). The mixture was sealed and then shaken at roomtemperature for 16 h. The reaction mixture was concentrated under astream of nitrogen at room temperature, dissolved in 500 μL of DMSO, andpurified by mass triggered preparative HPLC (Column: Waters Sunfire C18,5 μm, 19×50 mm; Mobile Phase: water (0.1% formic acid) and acetonitrile(0.1% formic acid) (15% to 100% acetonitrile in 6 min; flow rate: 23mL/min); Detector: UV 254/220 nm). The product-containing fractions werecombined and concentrated in a Genevac to affordN-hydroxy-4-pentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(1.3 mg, 16%). (ES, m/z) 265 [M+H]⁺, LC-MS R_(t) 1.20 min.

Example19—N-hydroxy-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide1,1-dioxide (I-79)

A half-dram vial was charged with methyl3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate 1,1-dioxide (0.2 M inN,N-dimethylacetamide, 250 μL, 50 μmol) and cesium carbonate (65 mg, 200μmol). Then a solution of 1-(bromomethyl)-4-(trifluoromethyl)benzene(0.2 M in N,N-dimethylacetamide, 500 μL, 100 mmol) was added. The vialwas sealed and shaken at 50° C. for 16 h, then the solvent was removedunder a stream of nitrogen. The residue was diluted with brine (500 μL)and extracted with ethyl acetate (2×500 μL). The combined organic layerswere dried under a stream of nitrogen. THF/methanol (3:1, 200 μL) wasadded to the residue. The vial was sealed and shaken at 50° C. for 15min to dissolve the residue, then cooled to room temperature.Hydroxylamine (150 μL, 50% v/v solution in water) was added, followed by1 N aqueous sodium hydroxide (100 μL). The mixture was sealed and thenshaken at room temperature for 16 h. The reaction mixture wasconcentrated under a stream of nitrogen at room temperature, thendissolved in 500 μL of DMSO and purified by mass triggered preparativeHPLC (Column: Waters Sunfire C18, 5 μm, 19×50 mm; Mobile Phase: water(0.1% formic acid) and acetonitrile (0.1% formic acid) (15% to 100%acetonitrile in 6 min; flow rate: 23 mL/min); Detector: UV 254/220 nm).The product-containing fractions were combined and concentrated in aGenevac to affordN-hydroxy-4-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide1,1-dioxide (8.0 mg, 40% yield). (ES, m/z) 401 [M+H]⁺.

The following compounds were synthesized according to the above protocolof Example 19.

HPLC Compd. LC-MS RT No. Structure IUPAC Name [M + H]⁺ (min) I-80

N-hydroxy-4-(4- methoxybenzyl)-3,4- dihydro-2H- benzo[b][1,4]thiazine-7-carboxamide-1,1-dioxide 363 0.92 I-81

N-hydroxy-4-(3- (trifluoromethyl)benzyl)- 3,4-dihydro-2H-benzo[b][1,4]thiazine-6- carboxamide-1,1-dioxide 401 1.09 I-82

N-hydroxy-4-(4- (methylsulfonyl)benzyl)- 3,4-dihydro-2H-benzo[b][1,4]thiazine-6- carboxamide-1,1-dioxide 411 0.66

Example20—4-benzyl-N-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-83)

Step-1: Methyl4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

1-(Chloromethyl)-4-methoxybenzene (0.035 ml, 0.249 mmol) was added to asolution of methyl2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (50 mg,0.226 mmol) and cesium carbonate (221 mg, 0.678 mmol) in DMF (2 mL), andthe reaction stirred overnight at ambient temperature. The reaction wasdiluted with ethyl acetate and washed with brine. The organic layer wasseparated and concentrated to give methyl4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 212 [M+H]⁺.

Step-2: Methyl4-benzyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Borane-methyl sulfide complex in 2-methyltetrahydrofuran (0.675 mL,0.675 mmol) was added to a solution of methyl4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(70 mg, 0.225 mmol) in THF (5 mL), and the reaction was placed on aheater/shaker at 50° C. for 3 hours. The reaction was cooled to roomtemperature and 2.5 mL of methanol was added and stirred overnight atambient temperature. The reaction mixture was concentrated to dryness togive methyl4-benzyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate asan orange residue which was used directly in the next step withoutfurther purification. MS: (ES, m/z): 298 [M+H]⁺.

Step-3:4-benzyl-N-hydroxy-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-benzyl-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (66mg, 0.222 mmol) was dissolved in MeOH/THF (1/1) (2 mL), and 50% aqueoushydroxyl amine (0.75 mL, 11.4 mmol) and 1 N aqueous sodium hydroxidesolution (0.75 mL, 0.75 mmol) were added. The resulting solution stirredfor 2 hours at ambient temperature, and was then concentrated todryness. The crude product was purified by Prep-HPLC with the followingconditions: Waters reversed phase HPLC (23 mL/min, 8 min gradient 0%-35%Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD 5 μm,19×50 mm column. The collected fractions were combined and lyophilizedto affordN-hydroxy-2-methyl-4-(4-(methylsulfonyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(12.8 mg, 0.034 mmol, 15%) as a grey solid. ¹H NMR (300 MHz, DMSO-d₆) δppm 10.92 (s, 1H) 8.81 (s, 1H) 7.20-7.42 (m, 5H) 7.12 (d, J=1.76 Hz, 1H)6.97 (dd, J=8.21, 1.76 Hz, 1H) 6.73 (d, J=8.21 Hz, 1H) 4.43-4.62 (m, 2H)4.22-4.32 (m, 1H) 3.39 (dd, J=12.02, 2.35 Hz, 1H) 3.08 (dd, J=12.17,8.06 Hz, 1H) 1.29 (d, J=6.16 Hz, 3H). MS: (ES, m/z): 299 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 20.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-84

N-hydroxy-4-(4- methoxybenzyl)-2- methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.93 (br s, 1 H) 8.81 (s, 1 H) 7.12- 7.27 (m, 3 H) 6.97 (dd, J = 8.21,1.76 (Hz, 1 H) 6.85-6.94 (m, 2 H) 6.72 (d, J = 8.21 Hz, 1 H) 4.34-4.54(m, 2 H) 4.19-4.29 (m, 1 H) 3.37 (br d, J = 2.35 Hz, 1 H) 3.01 (dd, J =11.87, 8.06 Hz, 1 H) 1.27 (d, J = 6.16 Hz, 3 H) 329 I-85

N-hydroxy-2-methyl-4- (4- (methylsulfonyl)benzyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.91 (br s, 1 H) 8.81 (s, 1 H) 7.90 (d, J = 8.21 Hz, 2 H) 7.55 (d, J =8.50 Hz, 2 H) 6.91-7.14 (m, 2 H) 6.76 (d, J = 7.92 Hz, 1 H) 4.51-4.78(m, 2 H) 4.31 (br d, J = 6.16 Hz, 1 H) 3.44 (br d, J = 9.67 Hz, 1 H)3.21 (s, 3 H) 3.12-3.19 (m, 1 H) 1.31 (d, J = 6.45 Hz, 3 H) 377

Example21—N-hydroxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-86)

Step-1: methyl4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Benzenesulfonyl chloride (43.9 mg, 0.248 mmol) andN,N-diisopropylethylamine (0.108 mL, 0.621 mmol) were added to asolution of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (40mg, 0.207 mmol) in acetonitrile (2 mL), and the reaction stirred atambient temperature overnight. The reaction was diluted with ethylacetate and washed with brine. The organic phase was separated andconcentrated to afford methyl4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 366 [M+S+H]⁺.

Step-2:N-hydroxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (60mg, 0.180 mmol) was dissolved in MeOH/THF (1/1) (2 mL), and 50% aqueoushydroxyl amine (0.5 mL, 7.57 mmol), and 1 N aqueous sodium hydroxidesolution (0.5 mL, 0.55 mmol) were added. The resulting solution stirredfor 2 hours at ambient temperature, and was then concentrated todryness. The crude product was purified by Prep-HPLC with the followingconditions: Waters reversed phase HPLC: 23 mL/min, 8 min gradient 0%-35%Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD 5 μm,19×50 mm column. The collected fraction was lyophilized to affordN-hydroxy-4-(phenylsulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (23 mg, 0.069 mmol, 38%) as an off-whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.16 (br s, 1H) 9.00 (s, 1H)8.19 (d, J=2.05 Hz, 1H) 7.55-7.76 (m, 5H) 7.47 (dd, J=8.50, 2.05 Hz, 1H)6.88 (d, J=8.50 Hz, 1H) 3.91 (t, J=4.40 Hz, 2H) 3.65-3.77 (m, 2H). MS:(ES, m/z): 335 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 21.

MS Compd. (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-87

N-hydroxy-4-((4- methoxyphenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.14 (br s, 1 H) 8.98 (br s, 1 H) 8.20 (d, J = 2.05 Hz, 1 H) 7.54-7.64(m, 2 H) 7.46 (dd, J = 8.50, 2.05 Hz, 1 H) 7.04- 7.14 (m, 2 H) 6.87 (d,J = 8.79 Hz, 1 H) 3.83-3.92 (m, 2 H) 3.80-3.83 (m, 3 H) 3.70-3.77 (m, 2H) 365

Example22—4-(4-((difluoromethyl)sulfonyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-88)

Step-1: Methyl4-(4-((difluoromethyl)sulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

1-(Bromomethyl)-4-((difluoromethyl)sulfonyl)benzene (68.8 mg, 0.241mmol) was added to a solution of methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (50 mg, 0.241mmol) and cesium carbonate (236 mg, 0.724 mmol) in DMF (2 mL), and thereaction stirred overnight at ambient temperature. The reaction wasdiluted with ethyl acetate and washed with brine. The organic phase wasseparated and concentrated to afford methyl4-(4-((difluoromethyl)sulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateas a residue which was used directly in the next step without furtherpurification. MS: (ES, m/z): 434 [M+Na+H]⁺.

Step-2:4-(4-((difluoromethyl)sulfonyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(4-((difluoromethyl)sulfonyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(90 mg, 0.219 mmol) was dissolved in MeOH/THF (1/1) (3 mL) and 50%aqueous hydroxyl amine (1 mL, 15.14 mmol) and 1 N aqueous sodiumhydroxide solution (1 mL, 1 mmol) were added. The resulting solutionstirred for 2 hours at ambient temperature, and was then concentrated todryness. The crude product was purified by Prep-HPLC with the followingconditions: Waters reversed phase HPLC (23 mL/min, 8 min gradient15%-65% Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD5 μm, 19×50 mm column). The collected fractions were combined andlyophilized to afford4-(4-((difluoromethyl)sulfonyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(37.7 mg, 0.091 mmol, 42%) as a fluffy white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.11 (br s, 1H) 8.98 (s, 1H) 7.96 (d, J=8.21 Hz, 2H)7.68 (d, J=8.21 Hz, 2H) 7.40-7.50 (m, 1H) 7.28-7.35 (m, 1H) 7.11 (d,J=8.21 Hz, 1H) 5.34 (s, 2H) 4.90 (s, 2H) 3.30 (s, 1H). MS: (ES, m/z):413 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 22.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-89

N-hydroxy-4-(4- methoxybenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 7-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.14 (br s, 1 H) 9.03 (br s, 1 H) 7.30-7.43 (m, 2 H) 7.11-7.25 (m, 3 H)6.88 (d, J = 8.79 Hz, 2 H) 5.11 (s, 2 H) 4.83 (s, 2 H) 3.71 (s, 3 H) 329I-90

N-hydroxy-4-(4- (methylsulfonyl) benzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 7-carboxamide N/A 377⁺ I-91

N-hydroxy-4-(4- methoxybenzyl)-2- methyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 7-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.14 (s, 1 H) 9.03 (s, 1 H) 7.05-7.40 (m, 5 H) 6.79-6.97 (m, 2 H) 5.10(s, 2 H) 4.80- 5.01 (m, 1 H) 3.71 (s, 3 H) 1.51 (d, J = 6.74 Hz, 3 H)343 I-92

N-hydroxy-2-methyl- 4-(4- (methylsulfonyl) benzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 7-carboxamide ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.15 (br s, 1 H) 9.04 (s, 1 H) 7.89 (d, J = 8.50 Hz, 2H) 7.52 (d, J = 8.21 Hz, 2 H) 7.34-7.45 (m, 2 H) 6.99-7.18 (m, 1 H)5.18-5.39 (m, 2 H) 4.98 (q, J = 6.64 Hz, 1 H) 3.20 (s, 3 H) 1.53 (d, J =6.74 Hz, 3 H) 391 I-93

4-(2-chloro-4- (methylsulfonyl) benzyl)-N-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.08(d, J = 1.76 Hz, 1 H) 7.80 (dd, J = 8.21, 1.76 Hz, 1 H) 7.29-7.45 (m, 2H) 7.15 (d, J = 1.47 Hz, 1 H) 6.95 (d, J = 8.21 Hz, 1 H) 5.16 (s, 2 H)4.84 (s, 2 H) 3.34 (s, 4 H) 411 I-94

N-hydroxy-4-(1-(4- (methylsulfonyl) phenyl)ethyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide 411 I-95

4-(1-(2- fluorophenyl)ethyl)- N-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.16 (s, 1 H) 9.00 (s, 1 H) 7.60 (t, J = 7.62 Hz, 1 H) 7.51 (d, J =1.76 Hz, 1 H) 7.26- 7.41 (m, 2 H) 7.18- 7.26 (m, 1 H) 7.01- 7.15 (m, 2H) 6.01 (q, J = 7.13 Hz, 1 H) 4.66 (d, J = 2.35 Hz, 2 H) 331 1.86 (d, J= 7.33 Hz, 3 H) I-96

4-(1-(2,6- difluorophenyl)ethyl)- N-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.21 (br s, 1 H) 9.06 (s, 1 H) 7.73 (d, J = 1.76 Hz, 1 H) 7.41 (dd, J =8.35, 1.91 Hz, 1 H) 7.27-7.38 (m, 1 H) 7.07 (d, J = 8.50 Hz, 1 H) 7.01(t, J = 8.79 Hz, 2 H) 5.88-6.12 (m, 1 H) 4.56-4.68 (m, 2 H) 1.84-1.94(m, 3 H) 349

Example23—N-hydroxy-4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-97)

Step-1: Methyl4-(1H-imidazole-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

A solution of methyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(300 mg, 1.55 mmol) and carbonyl diimidazole (277 mg, 1.708 mmol) in THF(10 mL) was heated at 80° C. for 8 days. The reaction was cooled toambient temperature and then concentrated to dryness. The residue wasdiluted with dichloromethane and washed with brine. The organic layerwas passed through an Isolute© phase separator and then concentrated toafford methyl4-(1H-imidazole-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 288 [M+H]⁺.

Step-2:1-(6-(Methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-3-methyl-1H-imidazol-3-iumiodide

Methyl iodide (0.9 mL, 14 mmol) was added to a solution of methyl4-(1H-imidazole-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(400 mg, 1.392 mmol) in acetonitrile (5 mL), and the reaction stirred atambient temperature for 48 hours. The reaction was concentrated toafford1-(6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-3-methyl-1H-imidazol-3-iumiodide as a yellow-brown solid which was used directly in the next stepwithout further purification. MS: (ES, m/z): 302 [M−1+H]⁺.

Step-3: Methyl4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Piperidine (0.013 mL, 0.128 mmol) and triethylamine (0.049 mL, 0.349mmol) were added to a solution of1-(6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-3-methyl-1H-imidazol-3-iumiodide (50 mg, 0.116 mmol) in chloroform (3 mL), and the reactionmixture stirred at ambient temperature overnight. The reaction wasdiluted with dichloromethane and washed with aqueous brine. The organiclayer was separated, passed through an Isolute© phase separator, andconcentrated to afford methyl4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 305 [M+H]⁺.

Step-4:N-hydroxy-4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-97)

Hydroxyl amine (50% aqueous solution, 0.3 mL, 4.54 mmol) and 1 N aqueoussodium hydroxide solution (0.3 mL, 0.300 mmol) were added to a solutionof methyl4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(30 mg, 0.099 mmol) in methanol (1.0 mL) and THF (1.0 mL). The reactionmixture stirred at ambient temperature for 2 hours, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC: 23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column. The collected fraction waslyophilized to affordN-hydroxy-4-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(10 mg, 0.033 mmol, 33%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δppm 11.00 (s, 1H) 8.93 (s, 1H) 7.53 (d, J=2.05 Hz, 1H) 7.27 (dd, J=8.50,2.05 Hz, 1H) 6.86 (d, J=8.50 Hz, 1H) 4.00-4.40 (m, 2H) 3.45-3.66 (m, 2H)3.30 (br d, J=5.57 Hz, 5H) 1.55 (br s, 6H). MS: (ES, m/z): 306 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 23:

Compd. LC-MS HPLC RT No. Structure IUPAC Name [M + H]⁺ (min) I-156

N-hydroxy-4- (2′,3′,5′,6′- tetrahydrospiro [indoline-3,4′- pyran]-1-carbonyl)-3,4- dihydro-2H- benzo[b][1,4] oxazine-6- carboxamide 410 0.97

Example24—N-hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-98)

Step-1: Methyl 3-(2-bromo-2-methylpropanamido)-4-hydroxybenzoate

2-Bromo-2-methylpropanoic acid (100 mg, 0.598 mmol) andN,N-diisopropylamine (0.313 mL, 1.795 mmol) were added to a solution ofmethyl 3-amino-4-hydroxybenzoate (100 mg, 0.598 mmol) in chloroform (5mL). 2-Chloro-1,3-dimethylimidazolinium chloride (DMC) (111 mg, 0.658mmol) was added, and the reaction stirred at ambient temperatureovernight. The reaction was diluted with dichloromethane and washed withbrine. The organic layer was passed through an Isolute© phase separatorand then concentrated to afford methyl3-(2-bromo-2-methylpropanamido)-4-hydroxybenzoate as semi solid whichwas used directly in the next step without further purification. MS(ESI, m/z): 316, 318 [M+H]⁺.

Step-2: methyl4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Potassium carbonate (79 mg, 0.569 mmol) was added to a solution ofmethyl 3-(2-bromo-2-methylpropanamido)-4-hydroxybenzoate (60 mg, 0.190mmol) in DMF (5 mL) and the reaction mixture was placed on a heatershaker at 50° C. for 2 hours. The reaction was cooled to ambienttemperature, and 1-(chloromethyl)-4-methoxybenzene (0.027 ml, 0.190mmol) was added. The reaction stirred at room temperature overnight. Thereaction was diluted with ethyl acetate and washed with brine. Theorganic layer was separated and concentrated, and the residue waspurified by column chromatography on silica gel (Biotage 25 g column,eluting with 20-60% ethyl acetate-hexane) to afford methyl4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.141 mmol, 74%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.50-7.69 (m,2H) 7.14 (dd, J=18.47, 8.50 Hz, 3H) 6.83-7.02 (m, 2H) 5.12 (s, 2H) 3.78(s, 3H) 3.72 (s, 3H) 1.51 (s, 6H). MS: (ES, m/z): 378 [M+Na+H]⁺.

Step-3:N-hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-98)

Methyl4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.141 mmol) was dissolved in methanol (1 mL) and THF (1 mL). 50%aqueous hydroxylamine (0.5 mL, 7.6 mmol) and 1N aqueous sodium hydroxidesolution (0.5 mL, 0.500 mmol) were added, and the reaction stirred atambient temperature for 2 hours. The reaction mixture was concentrated,and the crude product was purified by prep-HPLC with the followingconditions: Waters reversed phase HPLC: (23 mL/min, 8 min gradient15%-65% Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD5 μm, 19×50 mm column. The collected fractions were lyophilized toaffordN-hydroxy-4-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(24.8 mg, 0.070 mmol, 50%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δppm 11.12 (br s, 1H) 8.99 (s, 1H) 7.28-7.56 (m, 2H) 7.16 (d, J=8.79 Hz,2H) 7.04 (d, J=8.21 Hz, 1H) 6.90 (d, J=8.79 Hz, 2H) 5.10 (s, 2H) 3.71(s, 3H) 1.49 (s, 6H). MS: (ES, m/z): 357 [M+H]⁺.

Example25—2-ethyl-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-99)

Step-1: methyl2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

2-Bromobutanoic acid (0.032 mL, 0.299 mmol), N,N-diisopropylethylamine(0.157 mL, 0.897 mmol) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T₃P)(0.231 mL, 0.389 mmol) were added to a solution of methyl3-amino-4-hydroxybenzoate (50 mg, 0.299 mmol) in acetonitrile (2 mL),and the reaction stirred at ambient temperature overnight. The reactionwas diluted with ethyl acetate and washed with brine. The organic layerwas separated and concentrated, and the residue was purified via columnchromatography on silica gel (Biotage 10 gram column, eluting with 5-60%ethyl acetate-hexane) to afford methyl2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (13 mg,0.055 mmol, 18%) which was used directly in the next step. MS (ESI,m/z): 236 [M+H]⁺.

Step-2: methyl2-ethyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

1-(Chloromethyl)-4-methoxybenzene (7.49 μL, 0.055 mmol) and cesiumcarbonate (54.0 mg, 0.166 mmol) were added to a solution of methyl2-ethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (13 mg,0.055 mmol) in DMF (2 mL), and the reaction stirred at ambienttemperature overnight. The reaction mixture was diluted with ethylacetate and washed with brine. The organic layer was separated andconcentrated to afford methyl2-ethyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateas semi solid which was used directly in the next step without furtherpurification. MS (ESI, m/z): 356 [M+H]⁺.

Step-3:2-ethyl-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-99)

Methyl2-ethyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(20 mg, 0.056 mmol) was dissolved in methanol (0.5 mL) and THF (0.5 mL),and 50% aqueous hydroxyl amine (0.25 ml, 3.78 mmol) and 1N aqueoussodium hydroxide solution (0.25 mL, 0.250 mmol) were added. The reactionmixture stirred at ambient temperature for 2 hours and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC: (23 mL/min, 8min gradient 15%-65% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column. The collected fractions werelyophilized to afford2-ethyl-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(11.6 mg, 0.033 mmol, 57.8% yield) as a white solid. 1H NMR (300 MHz,DMSO-d6) δ ppm 11.13 (br s, 1H) 9.00 (br s, 1H) 7.33-7.47 (m, 2H) 7.18(d, J=8.50 Hz, 2H) 7.08 (d, J=8.21 Hz, 1H) 6.89 (d, J=8.50 Hz, 2H) 5.11(d, J=5.57 Hz, 2H) 4.79 (dd, J=7.62, 4.69 Hz, 1H) 3.71 (s, 3H) 1.77-1.95(m, 2H) 1.02 (t, J=7.48 Hz, 3H). MS: (ES, m/z): 357 [M+H]⁺.

Example26—N-hydroxy-2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-100)

Step-1: methyl 3-(2-bromo-3-methylbutanamido)-4-hydroxybenzoate

4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride(DMTMM) (83 mg, 0.299 mmol) was added to a solution of methyl3-amino-4-hydroxybenzoate (50 mg, 0.299 mmol) and2-bromo-3-methylbutanoic acid (54.1 mg, 0.299 mmol) in dichloromethane(2 mL), and the reaction stirred at ambient temperature overnight. Thereaction was diluted with dichloromethane and washed with brine. Theorganic layer was separated and filtered through an Isolute© phaseseparator. The filtrate was concentrated to afford methyl3-(2-bromo-3-methylbutanamido)-4-hydroxybenzoate which was used directlyin the next step without further purification. MS (ESI, m/z): 330, 332[M+H]⁺.

Step-2: methyl2-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Potassium carbonate (124 mg, 0.900 mmol) was added to a solution ofmethyl 3-(2-bromo-3-methylbutanamido)-4-hydroxybenzoate (99 mg, 0.300mmol) in DMF (3 mL), and the reaction was placed on a heater/shaker at80° C. overnight. The reaction was diluted with ethyl acetate and washedwith brine. The organic layer was separated and concentrated. Theresidue purified by column chromatography on silica gel (Biotage 10 gramcolumn, eluting with 0-10% methanol-dichloromethane) to afford methyl2-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (30mg, 0.120 mmol, 40% yield) as a colorless film. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 10.89 (s, 1H) 7.50-7.59 (m, 1H) 7.49 (s, 1H) 7.07 (d,J=8.21 Hz, 1H) 4.53 (d, J=4.98 Hz, 1H) 3.81 (s, 3H) 2.20 (dd, J=12.02,6.74 Hz, 1H) 1.03 (d, J=6.74 Hz, 3H) 0.92 (d, J=6.74 Hz, 3H). MS: (ES,m/z): 250 [M+H]⁺.

Step-3: methyl2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

1-(Chloromethyl)-4-methoxybenzene (0.016 ml, 0.120 mmol) and potassiumcarbonate (49.9 mg, 0.361 mmol) were added to a solution of methyl2-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (30mg, 0.120 mmol) in DMF (2 mL), and the reaction stirred at ambienttemperature overnight. The reaction mixture was diluted with ethylacetate and washed with brine. The organic layer was separated andconcentrated to afford methyl2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS (ESI, m/z): 370 [M+H]⁺.

Step-4:N-hydroxy-2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-100)

Methyl2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(40 mg, 0.108 mmol) was dissolved in methanol (1 mL) and THF (1 mL), and50% aqueous hydroxyl amine (0.5 ml, 7.57 mmol) and 1 N aqueous sodiumhydroxide solution (0.5 mL, 0.500 mmol) were added. The reaction stirredat ambient temperature for 2 hours and was then concentrated to dryness.The crude product was purified by Prep-HPLC with the followingconditions: Waters reversed phase HPLC: (23 mL/min, 8 min gradient15%-65% Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD5 μm, 19×50 mm column. The collected fractions were lyophilized toaffordN-hydroxy-2-isopropyl-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(15.4 mg, 0.042 mmol, 38%) as a fluffy white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.12 (br s, 1H) 8.99 (s, 1H) 7.35-7.49 (m, 2H) 7.19 (d,J=8.50 Hz, 2H) 7.08 (d, J=8.21 Hz, 1H) 6.90 (d, J=8.79 Hz, 2H) 5.00-5.22(m, 2H) 4.60 (d, J=6.45 Hz, 1H) 3.71 (s, 3H) 2.13-2.26 (m, 1H) 1.00 (dd,J=15.68, 6.89 Hz, 6H). MS: (ES, m/z): 371 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 26.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-101

N-hydroxy-4-(4- methoxybenzyl)-3- oxo-2-phenyl-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (s, 1 H) 9.01 (br s, 1 H) 7.39 (s, 6 H) 7.17 (dd, J = 18.32, 8.35Hz, 4 H) 6.84-6.92 (m, 2 H) 6.08 (s, 1 H) 5.18 (s, 2 H) 3.71 (s, 3 H)405 I-102

2-benzyl-N-hydroxy- 4-(4-methoxybenzyl)- 3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (br s, 1 H) 8.99 (s, 1 H) 7.44 (d, J = 1.76 Hz, 1 H) 7.39 (dd, J =8.50, 1.76 Hz, 1 H) 7.20-7.35 (m, 5 H) 7.15 (d, J = 8.79 Hz, 2 H) 6.97(d, J = 8.21 Hz, 1 H) 6.85-6.92 (m, 2 H) 5.02-5.21 (m, 3 H) 3.71 (s, 3H) 3.20- 3.28 (m, 1 H) 3.06- 3.17 (m, 1 H) 419 I-103

2-(tert-butyl)-N- hydroxy-4-(4- methoxybenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.11 (br s, 1 H) 8.99 (br s, 1 H) 7.46 (d, J = 1.76 Hz, 1 H) 7.39 (dd,J = 8.21, 1.76 Hz, 1 H) 7.24 (d, J = 8.79 Hz, 2 H) 7.06 (d, J = 8.50 Hz,1 H) 6.91 (d, J = 8.79 Hz, 2 H) 5.02-5.23 (m, 2 H) 4.59 (s, 1 H) 3.71(s, 3 H) 0.99 (s, 9 H) 385 I-157

N-hydroxy-4-(4- methoxybenzyl)-3- oxo-3,4- dihydrospiro[benzo[b][1,4]oxazine-2,1′- cyclobutane]-6- carboxamide 1H NMR (300 MHz, DMSO-d₆)δ ppm 11.12 (br s, 1 H) 9.01 (br s, 1 H) 7.34-7.51 (m, 2 H) 7.14 (dd, J= 14.66, 8.50 Hz, 3 H) 6.90 (d, J = 8.79 Hz, 2H) 5.11 (s, 2 H) 3.71 (s,3 H) 2.13-2.39 (m, 3 H) 1.91-2.10 (m, 1 H) 1.57-1.91 (m, 2 H) 369 I-158

N-hydroxy-4-(4- methoxybenzyl)-3- oxo-3,4- dihydrospiro[benzo[b][1,4]oxazine-2,1′- cyclohexane]-6- carboxamide None taken 397 I-159

4-(2-chloro-4- methoxybenzyl)-N- hydroxy-2,2- dimethyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide 1H NMR (300 MHz,DMSO-d₆) δ ppm 8.45-9.12 (m, 1 H) 7.41 (dd, J = 8.50, 1.76 Hz, 1 H) 7.24(d, J = 1.76 Hz, 1 H) 7.13 (d, J = 2.35 Hz, 1 H) 7.01 (d, J = 8.50 Hz, 1H) 6.77-6.92 (m, 2 H) 5.07 (s, 2 H) 3.75 (s, 3 H) 1.50 (s, 7 H) 391I-160

4-(2-fluoro-4- methoxybenzyl)-N- hydroxy-2,2- dimethyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide 1H NMR (300 MHz,DMSO-d₆) δ ppm 1.48 (s, 6 H) 3.73 (s, 3 H) 5.12 (s, 2 H) 6.73 (dd, J =8.65, 2.49 Hz, 1 H) 6.87 (dd, J = 12.46, 2.49 Hz, 1 H) 6.97 (t, J = 8.79Hz, 1 H) 7.06 (d, J = 8.79 Hz, 1 H) 7.42 (dd, J = 4.25, 2.49 Hz, 2 H)9.00 (br s, 1 H) 11.13 (br s, 1 H) 375 I-161

4-(4-chloro-2- fluorobenzyl)-N- hydroxy-2,2- dimethyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide 1H NMR (300 MHz,DMSO-d₆) δ ppm 1.49 (s, 6 H) 5.17 (s, 2 H) 6.98- 7.14 (m, 2 H) 7.25 (dd,J = 8.79, 1.76 Hz, 1 H) 7.31-7.41 (m, 1 H) 7.41-7.56 (m, 2 H) 9.00 (s, 1H) 11.13 (br s, 1 H) 379⁺

Example27—2-(2-aminoethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-104)

Step-1: methyl3-(2-bromo-4-(1,3-dioxoisoindolin-2-yl)butanamido)-4-hydroxybenzoate

4-(4,6-d4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-iumchloride (166 mg, 0.598 mmol) was added to a solution of methyl3-amino-4-hydroxybenzoate (100 mg, 0.598 mmol) and2-bromo-4-(1,3-dioxoisoindolin-2-yl)butanoic acid (187 mg, 0.598 mmol)in DMF (5 mL), and the reaction stirred overnight at ambienttemperature. The reaction mixture was diluted with ethyl acetate andwashed with brine. The organic layer was separated and concentrated toafford methyl3-(2-bromo-4-(1,3-dioxoisoindolin-2-yl)butanamido)-4-hydroxybenzoate asa thin film which was used directly in the next step without furtherpurification. MS (ESI, m/z): 461, 463 [M+H]⁺.

Step-2: methyl2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Potassium carbonate (243 mg, 1.756 mmol) was added to a solution ofmethyl3-(2-bromo-4-(1,3-dioxoisoindolin-2-yl)butanamido)-4-hydroxybenzoate(270 mg, 0.585 mmol) in DMF (5 mL), and the reaction was placed onheater/shaker at 50° C. overnight. The reaction mixture was diluted withethyl acetate and washed with brine. The resulting precipitate wascollected by suction filtration, rinsed with ethyl acetate, and dried toafford crude2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(240 mg). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.91 (br s, 1H) 7.74-7.94 (m,4H) 7.41-7.56 (m, 2H) 6.89 (d, J=8.21 Hz, 1H) 4.79 (dd, J=8.21, 3.81 Hz,1H) 3.74-3.87 (m, 5H) 2.07-2.34 (m, 2H). MS: (ES, m/z): 381 [M+H]⁺.

Step-3: methyl2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

1-(Chloromethyl)-4-methoxybenzene (0.089 mL, 0.631 mmol) and potassiumcarbonate (262 mg, 1.893 mmol) were added to a solution of methyl2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(240 mg, 0.631 mmol) in DMF (5 mL), and the reaction stirred at ambienttemperature overnight. The reaction mixture was diluted with ethylacetate and washed with brine. The organic layer was separated andconcentrated to afford methyl2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateas a white solid which was used directly in the next step withoutfurther purification. MS (ESI, m/z): 501 [M+H]⁺.

Step-4: methyl2-(2-aminoethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Hydrazine hydrate (0.046 mL, 0.799 mmol) was added to a solution ofmethyl2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (200 mg, 0.400 mmol) in ethanol (2 mL).The reaction mixture was heated at 50° C. for 3 hours, and then cooledto room temperature. Ethyl acetate was added, and the mixture was washedwith brine. The organic layer was separated and concentrated to affordmethyl2-(2-aminoethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS (ESI, m/z): 371 [M+H]⁺.

Step-5:2-(2-aminoethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-104)

Methyl2-(2-aminoethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(30 mg, 0.081 mmol) was dissolved in methanol (1 mL) and THF (1 mL), and50% aqueous hydroxyl amine solution (0.268 mL, 4.05 mmol) and 1N aqueoussodium hydroxide solution (0.243 ml, 0.243 mmol) were added. Thereaction stirred at ambient temperature for 2 hours, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column. The collected fractions werelyophilized to afford2-(2-aminoethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(13.4 mg, 0.036 mmol, 44%) as the formic acid salt (peach coloredsolid). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.35 (s, 1H) 7.36-7.49 (m, 2H)7.18 (d, J=8.50 Hz, 2H) 7.10 (d, J=8.21 Hz, 1H) 6.89 (d, J=8.79 Hz, 2H)5.11 (s, 2H) 4.97 (dd, J=8.79, 4.10 Hz, 1H) 3.71 (s, 3H) 3.33 (br s, 2H)2.89 (t, J=7.18 Hz, 2H) 1.93-2.18 (m, 2H). MS: (ES, m/z): 372 [M+H]⁺.

Example28—2-(2-(dimethylamino)ethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-105)

Step-1: methyl2-(2-(dimethylamino)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Potassium carbonate (56.0 mg, 0.405 mmol) and methyl iodide (0.017 mL,0.270 mmol) were added to a solution of methyl2-(2-aminoethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.135 mmol) in DMF (2 mL), and the reaction stirred overnight atambient temperature. The reaction was diluted with ethyl acetate andwashed with brine. The organic layer was separated and concentrated toafford methyl2-(2-(dimethylamino)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateas a thin film which was used directly in the next step without furtherpurification. MS (ESI, m/z): 399 [M+H]⁺.

Step-2:2-(2-(dimethylamino)ethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-105)

Methyl2-(2-(dimethylamino)ethyl)-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(51.8 mg, 0.130 mmol) was dissolved in methanol (1 mL) and THF (1 mL),and 50% aqueous hydroxyl amine solution (0.5 mL, 7.57 mmol) and 1Naqueous sodium hydroxide solution (0.5 mL, 0.5 mmol) were added. Thereaction stirred at ambient temperature for 2 hours and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 m, 19×50 mm column. The collected fractions werelyophilized to afford2-(2-(dimethylamino)ethyl)-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(1 mg, 2.504 μmol, 2% yield) as a white solid. MS: (ES, m/z): 400[M+H]⁺.

Example29—1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-7-carboxamide(I-106)

Step-1. methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate

Concentrated hydrochloric acid (1 drop) was added to a solution of2-bromo-1H-benzo[d]imidazole (50 mg, 0.254 mmol) and methyl1,2,3,4-tetrahydroquinoline-7-carboxylate (48.5 mg, 0.254 mmol) inethanol (2 mL). The reaction vessel was sealed and the mixture washeated at 150° C. in the microwave for 3 hours. The reaction mixture wasconcentrated to afford methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 308 [M+H]⁺.

Step-2.1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-7-carboxamide(I-106)

Methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate(78 mg, 0.25 mmol) was dissolved in methanol/THF (1/2, 3 mL), and 50%aqueous hydroxyl amine solution (0.5 mL, 7.57 mmol) and 1N aqueoussodium hydroxide solution (0.5 mL, 0.55 mmol) were added. The resultingsolution was stirred for 2 hours at ambient temperature and thenconcentrated to dryness. Ethyl acetate and 1 N aqueous HCl solution wereadded and the solution was stirred for 30 minutes. The resulting solidwas collected by suction filtration, washed with ethyl acetate, anddried to afford1-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-1,2,3,4-tetrahydroquinoline-7-carboxamide(0.024 g, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 13.45 (br s, 1H) 11.22(s, 1H) 9.11 (s, 1H) 8.02 (s, 1H) 7.59 (d, J=7.62 Hz, 1H) 7.50 (dd,J=5.86, 3.22 Hz, 2H) 7.39 (d, J=7.92 Hz, 1H) 7.33 (dd, J=5.72, 3.08 Hz,2H) 3.94 (t, J=6.30 Hz, 2H) 2.83 (br t, J=6.45 Hz, 2H) 2.04 (br t,J=6.30 Hz, 2H). MS (ESI, m/z): MS: (ES, m/z): 309 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 29.

MS (ES, Compd. m/z) No. Structure IUPAC Name [M + H]⁺ I-107

1-(1H-benzo[d]imidazol-2-yl)-N- hydroxy-1,2,3,4-tetrahydroquinoline-6-carboxamide 309 I-108

4-(1H-benzo[d]imidazol-2-yl)-N- hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide 311 I-109

4-(1H-benzo[d]imidazol-2-yl)-N- hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 311

Example30—N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxamide(I-110)

Step-1: methyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate

Concentrated hydrochloric acid (1 drop) was added to a solution of2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (100 mg, 0.392 mmol) andmethyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (75 mg, 0.392 mmol) inethanol (2 mL). The reaction vessel was sealed and the mixture washeated at 155° C. in the microwave for 3 hours. The reaction mixture wasconcentrated to dryness, and the residue was purified via columnchromatography on silica gel (Biotage 10 gram column, eluting with10-60% ethyl acetate-hexane) to afford methyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 366 [M+H]⁺.

Step-2:N-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

Methyl1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate(10 mg, 0.027 mmol) was dissolved in methanol/THF (1/2, 1.5 mL), and 50%aqueous hydroxyl amine solution (0.25 mL, 3.78 mmol) and 1N aqueoussodium hydroxide solution (0.25 mL, 0.25 mmol) were added. The resultingsolution was stirred for 2 hours at ambient temperature and thenconcentrated to dryness. The residue was purified via preparative-HPLC(eluting with acetonitrile and water) to affordN-hydroxy-1-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxamide(0.0015 g, 10%) as a white solid. MS (ESI, m/z): 367 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 30.

MS (ES, Compd. m/z) No. Structure IUPAC Name [M + H]⁺ I-111

N-hydroxy-1-(1-(2- methoxyethyl)-1H- benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-6- carboxamide 367

Example31—N-hydroxy-1-(4-methoxybenzoyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide(I-112)

Step-1: methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate

N,N-Diisopropylethyl amine (114 uL, 0.654 mmol) and2-chloro-1,3-dimethylimidazolinium chloride (DMC) (66.4 mg, 0.392 mmol)were added to a solution of methyl1,2,3,4-tetrahydroquinoline-7-carboxylate (50 mg, 0.261 mmol) and4-methoxybenzoic acid (40 mg, 0.261 mmol) in chloroform (2 mL), and thereaction stirred at ambient temperature overnight. The reaction wasdiluted with dichloromethane and washed with brine. The organic layerwas separated and filtered through an Isolute© phase separator. Thefiltrate was concentrated to afford methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 326 [M+H]⁺.

Step-2:N-hydroxy-1-(4-methoxybenzoyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide

Methyl1-(1H-benzo[d]imidazol-2-yl)-1,2,3,4-tetrahydroquinoline-7-carboxylate(50 mg, 0.154 mmol) was dissolved in methanol/THF (1/4, 2.5 mL), and 50%aqueous hydroxyl amine solution (0.5 mL, 7.57 mmol) and 1N aqueoussodium hydroxide solution (0.5 mL, 0.5 mmol) were added. The resultingsolution was stirred for 2 hours at ambient temperature and thenconcentrated to dryness. The residue was purified by preparative-HPLCwith the following conditions: Waters reversed phase HPLC: 25 mL/min, 6min gradient 25%-65% Acetonitrile, 0.1% formic acid on a Waters SunfireC18, 5 μm, 19×50 mm column to affordN-hydroxy-1-(4-methoxybenzoyl)-1,2,3,4-tetrahydroquinoline-7-carboxamide.MS: (ES, m/z): 327 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 31.

MS Compd. (ES, m/z No. Structure IUPAC Name ¹H NMR [M + H]) I-113

N-hydroxy-4-(4- methoxybenzoyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.01 (br s, 1 H) 8.89 (s,1 H) 7.80 (s, 1 H) 7.54 (d, J = 8.79 Hz, 2 H) 7.39 (dd, J = 8.50, 2.05Hz, 1 H) 6.97 (dd, J = 17.15, 8.65 Hz, 3 H) 4.32 (t, J = 4.40 Hz, 2 H)3.85-3.94 (m, 2 H) 3.81 (s, 3 H) 329 I-114

4- (cyclohexanecarbonyl)- N-hydroxy-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.08 (br s, 1 H) 8.93 (br s, 1 H) 8.12 (br s, 1 H) 7.44 (br d, J = 7.92Hz, 1 H) 6.92 (d, J = 8.50 Hz, 1 H) 4.29 (t, J = 4.54 Hz, 2 H) 3.90 (t,J = 4.40 Hz, 2 H) 2.77-2.93 (m, 1 H) 1.60-1.83 (m, 5 H) 1.09-1.52 (m, 5H) 305

Example32—N-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-115)

Step-1: methyl4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

4-Methoxybenzaldehyde (31.5 μL, 0.259 mmol) and acetic acid (50 μL,0.873 mmol) were added to a solution of methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (50.0 mg, 0.259 mmol)in 1,2-dichloroethane (2 mL), and the reaction mixture was placed on aheater/shaker at 50° C. for 2 hours. Sodium triacetoxyborohydride (137mg, 0.647 mmol) was added, and the reaction was placed on theheater/shaker at 50° C. overnight. The reaction was diluted withdichloromethane, washed with brine, and passed through an Isolute© phaseseparator. The filtrate was concentrated and purified by columnchromatography on silica gel (Biotage 10 gram column, eluting with10-60% ethyl acetate-hexanes) to afford methyl4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step MS: (ES, m/z): 314 [M+H]⁺.

Step-2:N-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(25 mg, 0.154 mmol) was dissolved in methanol/THF (1/4, 2.5 mL), and 50%aqueous hydroxyl amine solution (0.25 mL, 3.78 mmol) and 1N aqueoussodium hydroxide solution (0.25 mL, 0.275 mmol) were added. Theresulting solution stirred for 2 hours at ambient temperature, and wasthen concentrated to dryness. The crude product was purified bypreparative-HPLC with the following conditions: Waters reversed phaseHPLC: 25 mL/min, 6 min gradient 25%-65% Acetonitrile, 0.1% formic acidon a Waters Sunfire C18, 5 μm, 19×50 mm column to affordN-hydroxy-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide.MS: (ES, m/z): 315 [M+H]⁺.

Example33—4-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-116)

Step-1: methyl4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Potassium carbonate (86 mg, 0.621 mmol) was added to a solution ofmethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (30 mg, 0.155mmol) in DMF (2 mL). (Bromomethyl)benzene (0.028 mL, 0.233 mmol) wasadded, and the reaction was placed on a heater/shaker at 80° C.overnight. The reaction mixture was cooled to room temperature, dilutedwith ethyl acetate, and washed with brine. The organic layer wasseparated and concentrated to afford methyl4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate which wasused directly in the next step without further purification. MS: (ES,m/z): 284 [M+H]⁺.

Step-2:4-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl 4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (45mg, 0.159 mmol) was dissolved in methanol/THF (1/1, 2 mL), and 50%aqueous hydroxyl amine solution (0.5 mL, 7.57 mmol) and 1N aqueoussodium hydroxide solution (0.5 mL, 0.55 mmol) were added. The resultingsolution stirred for 2 hours at ambient temperature, and was thenconcentrated to dryness. The crude product was purified bypreparative-HPLC with the following conditions: Waters reversed phaseHPLC (23 mL/min, 8 min gradient 15%-65% Acetonitrile, 0.1% formic acidon a Waters XBridge Prep C18 OBD 5 μm, 19×50 mm column. The desiredfractions were lyophilized to afford4-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (10mg, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.91 (br s, 1H) 8.80 (br s,1H) 7.20-7.40 (m, 5H) 7.12 (d, J=2.05 Hz, 1H) 6.97 (dd, J=8.21, 2.05 Hz,1H) 6.73 (d, J=8.21 Hz, 1H) 4.53 (s, 2H) 4.16-4.30 (m, 2H) 3.35-3.40 (m,2H). MS: (ES, m/z): 285 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 33.

MS Compd. (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H] I-117

N-hydroxy-4-(4- methylbenzyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.92 (br s, 1 H) 8.81 (brs, 1 H) 7.10- 7.23 (m, 5 H) 6.97 (dd, J = 8.21, 1.47 Hz, 1 H) 6.72 (d, J= 8.21 Hz, 1 H) 4.47 (s, 2 H) 4.19-4.25 (m, 2 H) 3.36 (br s, 2 H) 2.27(s, 3 H) 299 I-118

4-(4-chlorobenzyl)- N-hydroxy-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide N/A 319 I-119

N-hydroxy-4-(4- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.91 (br s, 1 H) 8.80 (s, 1 H) 7.72 (d, J = 8.50 Hz, 2 H) 7.51 (d, J =8.21 Hz, 2 H) 6.93-7.08 (m, 2 H) 6.75 (d, J = 8.21 Hz, 1 H) 4.63 (s, 2H) 4.21- 4.34 (m, 2 H) 3.37-3.50 (m, 2 H) 353 I-120

N-hydroxy-4-(4- (methylsulfonyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.91 (s, 1 H) 8.81 (s, 1 H) 7.90 (d, J = 8.50 Hz, 2 H) 7.55 (d, J =8.50 Hz, 2 H) 6.94-7.05 (m, 2 H) 6.76 (d, J = 7.92 Hz, 1 H) 4.65 (s, 2H) 4.18- 4.36 (m, 2 H) 3.43 (br s, 2 H) 3.21 (s, 3 H) 363 I-121

N-hydroxy-4-(3- methoxybenzyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.92 (s, 1 H) 8.79 (s, 1H) 7.26 (t, J = 7.92 Hz, 1 H) 7.12 (d, J = 2.05 Hz, 1 H) 6.98 (dd, J =8.21, 1.47 Hz, 1 H) 6.79- 6.91 (m, 3 H) 6.73 (d, J = 8.21 Hz, 1 H) 4.49(s, 2 H) 4.23 (br d, J = 4.40 Hz, 2 H) 3.70-3.74 (m, 3 H) 3.38 (br d, J= 4.69 Hz, 2 H) 315 I-122

N-hydroxy-4-(3- methylbenzyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.92 (s, 1 H) 8.79 (s, 1H) 7.18- 7.25 (m, 1 H) 7.05-7.14 (m, 4 H) 6.97 (dd, J = 8.21, 2.05 Hz, 1H) 6.73 (d, J = 8.21 Hz, 1 H) 4.48 (s, 2 H) 4.17-4.28 (m, 2 H) 3.33-3.38 (m, 2 H) 2.27-2.31 (m, 3 H) 299 I-123

4-(3-chlorobenzyl)- N-hydroxy-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.92 (s, 1 H) 8.80 (s, 1H) 7.21- 7.45 (m, 4 H) 7.06 (d, J = 1.76 Hz, 1 H) 7.00 (dd, J = 8.21,1.76 Hz, 1 H) 6.74 (d, J = 7.92 Hz, 1 H) 4.53 (s, 2 H) 4.17-4.31 (m, 2H) 3.36-3.46 (m, 2 H) 319 I-124

N-hydroxy-4-(3- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.91 (s, 1 H) 8.80 (d, J = 1.76 Hz, 1 H) 7.54-7.70 (m, 4 H) 7.09 (d, J= 1.47 Hz, 1 H) 7.01 (dd, J = 8.21, 1.17 Hz, 1 H) 6.75 (dd, J = 8.21,0.88 Hz, 1 H) 4.62 (s, 2 H) 4.20-4.32 (m, 2 H) 3.40 (t, J = 4.40 Hz, 2H) 353 I-125

N-hydroxy-4-(3- (methylsulfonyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.92 (s, 1 H) 8.80 (s, 1 H) 7.76- 7.92 (m, 2 H) 7.63 (d, J = 4.98 Hz, 2H) 7.08 (d, J = 1.76 Hz, 1 H) 7.01 (dd, J = 8.06, 1.91 Hz, 1 H) 6.76 (d,J = 8.21 Hz, 1 H) 4.64 (s, 2 H) 4.26 (br d, J = 4.98 Hz, 2 H) 3.43 (brd, J = 4.40 Hz, 2 H) 3.16-3.25 (m, 3 H) 363 I-126

N-hydroxy-4-(2- methoxybenzyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.90 (br s, 1 H) 8.76 (d,J = 2.05 Hz, 1 H) 7.22-7.44 (m, 2 H) 6.87-7.05 (m, 4 H) 6.72 (d, J =8.21 Hz, 1 H) 4.46 (s, 2 H) 4.14-4.27 (m, 2 H) 3.82- 3.85 (m, 3 H)3.36-3.45 (m, 2 H) 315 I-127

N-hydroxy-4-(2- methylbenzyl)-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.90 (s, 1 H) 8.79 (br s,1 H) 7.06- 7.24 (m, 4 H) 6.94-7.01 (m, 2 H) 6.75 (d, J = 8.79 Hz, 1 H)4.46 (s, 2 H) 4.20- 4.29 (m, 2 H) 3.24-3.33 (m, 3 H) 2.32 (s, 3 H) 299I-128

4-(2-chlorobenzyl)- N-hydroxy-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.92 (s, 1 H) 8.78 (d, J= 1.47 Hz, 1 H) 7.44-7.57 (m, 1 H) 7.33 (s, 1 H) 7.18-7.37 (m, 3 H)6.86-7.04 (m, 2 H) 6.77 (d, J = 8.21 Hz, 1 H) 4.58 (s, 2 H) 4.17-4.35(m, 2 H) 3.43 (t, J = 4.25 Hz, 2 H) 319 I-129

N-hydroxy-4-(2- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.90 (br s, 1 H) 8.81 (br s, 1 H) 7.42- 7.87 (m, 4 H) 6.68-7.06 (m, 3H) 4.61-4.73 (m, 2 H) 4.23-4.34 (m, 2 H) 3.40- 3.47 (m, 2 H) 353 I-130

N-hydroxy-4-(2- (methylsulfonyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.88 (s, 1 H) 8.75 (d, J = 1.76 Hz, 1 H) 7.99 (dd, J = 7.77, 1.32 Hz, 1H) 7.41-7.73 (m, 3 H) 6.69-7.05 (m, 3 H) 4.80- 4.99 (m, 2 H) 4.14-4.35(m, 2 H) 3.35-3.48 (m, 2 H) 3.31 (s, 3 H) 363 I-131

4-(2- (difluoromethoxy) benzyl)-N-hydroxy- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.91 (s, 1 H) 8.78 (d, J = 1.47 Hz, 1 H) 7.31-7.39 (m, 1 H) 7.12- 7.31(m, 4 H) 6.93-7.06 (m, 2 H) 6.75 (d, J = 7.92 Hz, 1 H) 4.54 (s, 2 H)4.21- 4.31 (m, 2 H) 3.39 (t, J = 4.40 Hz, 2 H) 351 I-132

4-(3- (difluoromethoxy) benzyl)-N-hydroxy- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.92 (s, 1 H) 8.80 (d, J = 2.05 Hz, 1 H) 7.36-7.49 (m, 1 H) 6.92- 7.25(m, 6 H) 6.74 (d, J = 8.21 Hz, 1 H) 4.54 (s, 2 H) 4.25 (dd, J = 4.98,3.81 Hz, 2 H) 3.34-3.43 (m, 2 H) 351 I-133

4- (cyclohexylmethyl)- N-hydroxy-3,4- dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.98 (br s, 1 H) 8.84 (s,1 H) 7.02 (d, J = 1.76 Hz, 1 H) 6.92 (dd, J = 8.21, 1.76 Hz, 1 H) 6.68(d, J = 8.21 Hz, 1 H) 4.13- 4.19 (m, 2 H), 3.31 (s, 2 H) 3.08 (d, J =6.74 Hz, 2 H) 1.70 (br d, J = 10.55 Hz, 6 H) 1.08-1.30 (m, 3 H) 0.96 (brd, J = 10.85 Hz, 2 H) 291 I-134

4-(2-chloro-4- (methylsulfonyl) benzyl)-N-hydroxy-3, 4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.93 (br s, 1 H) 8.81 (s, 1 H) 8.05 (d, J = 1.76 Hz, 1 H) 7.84 (dd, J =8.06, 1.91 Hz, 1 H) 7.49 (d, J = 8.21 Hz, 1 H) 7.03 (dd, J = 8.35, 1.91Hz, 1 H) 6.85 (d, J = 2.05 Hz, 1 H) 6.79 (d, J = 8.21 Hz, 1 H) 4.67 (s,2 H) 4.25-4.35 (m, 2 H) 3.49 (br d, J = 3.81 Hz, 2 H) 3.34 (s, 3 H) 397I-135

N-hydroxy-4-(1-(4- (methylsulfonyl) phenyl)ethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.94 (s, 1 H) 8.84 (s, 1 H) 7.91 (d, J = 8.50 Hz, 2 H) 7.64 (d, J =8.50 Hz, 2 H) 6.50-7.34 (m, 3 H) 5.27 (br d, J = 7.33 Hz, 1 H) 4.09-4.24(m, 2 H) 3.31 (br s, 2 H) 3.21 (s, 3 H) 1.56 (br d, J = 6.74 Hz, 3 H)377 I-136

4-(1-(2- chlorophenyl)ethyl)- N-hydroxy-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.94 (br s, 1 H) 8.81 (s, 1 H) 7.44- 7.56 (m, 2 H) 7.29-7.41 (m, 2 H)7.18 (d, J = 1.76 Hz, 1 H) 6.94 (dd, J = 8.21, 1.76 Hz, 1 H) 6.71 (d, J= 8.21 Hz, 1 H) 5.26 (q, J = 6.94 Hz, 1 H) 4.00-4.21 (m, 2 H) 3.30 (s, 1H) 3.31 (br s, 1 H) 2.97-3.14 (m, 1 333 H) 1.51 (d, J = 7.04 Hz, 3 H)I-137

N-hydroxy-4-(4- (methylsulfonyl)-2- (trifluoromethyl)benzyl)-3,4-dihydro- 2H- benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300MHz, DMSO-d₆) δ ppm 10.91 (br s, 1 H) 8.79 (s, 1 H) 8.06- 8.34 (m, 2 H)7.74 (d, J = 8.35 Hz, 1 H) 7.02 (dd, J = 8.35, 1.76 Hz, 1 H) 6.72- 6.89(m, 2 H) 4.78 (s, 2 H) 4.33 (br d, J = 3.52 Hz, 2 H) 3.49 (br s, 2 H)3.31 (s, 3 H) 431 I-138

N-hydroxy-4-(3- methoxy-4- (methylsulfonyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.93 (br s, 1 H) 8.82 (s, 1 H) 7.65- 7.88 (m, 1 H) 7.17-7.29 (m, 1 H)6.85-7.12 (m, 3 H) 6.75 (d, J = 8.21 Hz, 1 H) 4.45-4.67 (m, 2 H) 4.28(br s, 2 H) 3.94 (s, 3 H) 3.43 (br s, 2 H) 3.22 (s, 3 H) 393 I-139

N-hydroxy-4-(4- methoxy-3- (methylsulfonyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.94 (br s, 1 H) 8.83 (br s, 1 H) 7.76 (d, J = 2.05 Hz, 1 H) 7.59 (dd,J = 8.50, 2.05 Hz, 1 H) 7.28 (d, J = 8.50 Hz, 1 H) 7.12 (d, J = 1.76 Hz,1 H) 7.00 (dd, J = 8.21, 1.76 Hz, 1 H) 6.74 (d, J = 8.21 Hz, 1 H) 4.54(s, 2 H) 4.23 (br d, J = 4.10 Hz, 2 H) 3.86-3.97 (m, 3 H) 3.36 (br s, 2H) 3.24 (s, 3 H) 393

Example34—4-benzoyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-140)

Step-1: methyl4-benzoyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Triethylamine (0.065 mL, 0.466 mmol) and benzoyl chloride (0.022 mL,0.186 mmol) were added to a solution of methyl3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (30 mg, 0.155 mmol) in1,2-dichloroethane (2 mL), and the reaction stirred at ambienttemperature overnight. The reaction was diluted with dichloromethane andwashed with brine. The organic layer was passed through an Isolute©phase separator, and then concentrated to afford a quantitative yield ofmethyl 4-benzoyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate whichwas used directly in the next step without further purification. MS:(ES, m/z): 298 [M+H]⁺.

Step-2:4-benzoyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl 4-benzoyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (45mg, 0.151 mmol) was dissolved in methanol/THF (1/1, 3 mL), 50% aqueoushydroxyl amine solution (0.5 mL, 7.57 mmol) and 1N aqueous sodiumhydroxide solution (0.5 mL, 0.55 mmol) were added, and the resultingsolution stirred for 2 hours at ambient temperature. The reactionmixture was concentrated, and the crude product was purified bypreparative-HPLC with the following conditions: Waters reversed phaseHPLC: 23 mL/min, 8 min gradient 0%-35% Acetonitrile, 0.1% formic acid ona Waters XBridge Prep C18 OBD 5 μm, 19×50 mm column. The collectedfraction was lyophilized to afford4-benzoyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(13.5 mg, 30%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.00 (br s, 1H) 8.88 (s, 1H) 7.80-8.01 (m, 2H) 7.35-7.66 (m, 7H) 6.95(d, J=8.79 Hz, 1H) 4.28-4.38 (m, 2H) 3.80-3.93 (m, 2H). MS: (ES, m/z):299 [M+H]⁺.

Example35—N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-141)

Step-1: methyl4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Sodium hydride (23.17 mg, 0.579 mmol) was added to a solution of methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (100 mg, 0.483mmol) in DMF (3 mL), and the reaction stirred for 5 minutes.1-(Chloromethyl)-4-methoxybenzene (0.068 mL, 0.483 mmol) was added, andthe reaction stirred at ambient temperature overnight. The reactionmixture was diluted with ethyl acetate and washed with brine. Theorganic layer was separated and concentrated to afford a quantitativeyield of methyl4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylatewhich was used directly in the next step without further purification.MS: (ES, m/z): 328 [M+H]⁺.

Step 2:N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(150 mg, 0.458 mmol) was dissolved in methanol/THF (1/1, 4 mL), 50%aqueous hydroxyl amine solution (1.5 mL, 22.7 mmol) and 1N aqueoussodium hydroxide solution (1.5 mL, 1.5 mmol) were added, and theresulting solution stirred for 2 hours at ambient temperature. Thereaction mixture was concentrated, and the crude product was purified bypreparative-HPLC with the following conditions: Waters reversed phaseHPLC: 23 mL/min, 8 min gradient 0%-35% Acetonitrile, 0.1% formic acid ona Waters XBridge Prep C18 OBD 5 μm, 19×50 mm column. The collectedfraction was lyophilized to affordN-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(6.7 mg, 4%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (s, 1H) 8.99 (s, 1H) 7.33-7.51 (m, 2H) 7.21 (d, J=8.50 Hz, 2H)7.06 (d, J=8.50 Hz, 1H) 6.89 (d, J=8.79 Hz, 2H) 5.11 (s, 2H) 4.85 (s,2H) 3.71 (s, 3H). MS: (ES, m/z): 329 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 35.

MS (ES, Compd. m/z) No. Structure IUPAC Name ¹H NMR [M + H] I-142

N-hydroxy-4-(4- (methylsulfonyl) benzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (s, 1 H) 8.98 (s, 1 H) 7.90 (d, J = 8.21 Hz, 2 H) 7.56 (d, J =8.50 Hz, 2 H) 7.28- 7.46 (m, 2 H) 7.10 (d, J = 8.21 Hz, 1 H) 5.29 (s, 2H) 4.83-4.91 (m, 2 H) 3.21 (s, 3 H) 377 I-143

4-(3- chlorobenzyl)-N- hydroxy-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.13 (br s, 1 H)8.99 (br s, 1 H) 7.52-7.72 (m, 4 H) 7.42 (dd, J = 8.35, 1.91 Hz, 1 H)7.37 (d, J = 1.76 Hz, 1 H) 7.09 (d, J = 8.21 Hz, 1 H) 5.28 (s, 2 H) 4.90(s, 2 H) 333 I-144

N-hydroxy-3-oxo- 4-(3- (trifluoromethyl) benzyl)-3,4-dihydro- 2H-benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (br s, 1 H) 8.99 (br s, 1 H) 7.51-7.72 (m, 4 H) 7.42 (dd, J =8.35, 1.91 Hz, 1 H) 7.37 (d, J = 1.76 Hz, 1 H) 7.09 (d, J = 8.21 Hz, 1H) 5.28 (s, 2 H) 4.90 (s, 2 H) 367 I-145

N-hydroxy-4-(3- (methylsulfonyl) benzyl)-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.12 (br s, 1 H) 8.98 (br s, 1 H) 7.95 (s, 1 H) 7.84 (dt, J = 7.33,1.76 Hz, 1 H) 7.54- 7.68 (m, 2 H) 7.40- 7.46 (m, 1 H) 7.39 (d, J = 2.05Hz, 1 H) 7.09 (d, J = 8.21 Hz, 1 H) 5.30 (s, 2 H) 4.90 (s, 2 H) 3.22 (s,3 H) 377 I-146

N-hydroxy-3-oxo- 4-(3- (trifluoromethoxy) benzyl)-3,4- dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.11 (br s, 1 H) 8.98 (br s, 1 H) 7.45-7.52 (m, 1 H) 7.42 (dd, J =8.35, 1.91 Hz, 1 H) 7.37 (d, J = 1.76 Hz, 1 H) 7.23-7.33 (m, 3 H) 7.09(d, J = 8.21 Hz, 1 H) 5.23 (s, 2 H) 4.89 (s, 2 H) 383 I-147

4-(2- chlorobenzyl)-N- hydroxy-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.15 (br s, 1 H)8.97 (br s, 1 H) 7.55 (dd, J = 7.92, 1.47 Hz, 1 H) 7.44 (dd, J = 8.35,1.91 Hz, 1 H) 7.17-7.39 (m, 3 H) 7.04-7.14 (m, 2 H) 5.17 (s, 2 H)4.85-4.96 (m, 2 H) 333 I-148

N-hydroxy-4-(2- methylbenzyl)-3- oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.10 (br s, 1 H)8.95 (s, 1 H) 7.41 (dd, J = 8.35, 1.91 Hz, 1 H) 7.04-7.29 (m, 5 H) 6.89(d, J = 6.74 Hz, 1 H) 5.09 (s, 2 H) 4.90 (s, 2 H) 3.33 (s, 3 H) 313I-149

4- (cyclohexylmethyl)- N-hydroxy-3- oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.25 (br s, 1 H)9.06 (br s, 1 H) 7.53 (d, J = 2.05 Hz, 1 H) 7.44 (dd, J = 8.50, 1.76 Hz,1 H) 7.07 (d, J = 8.21 Hz, 1 H) 4.70 (s, 2 H) 3.83 (d, J = 7.33 Hz, 2 H)1.61 (br d, J = 14.07 Hz, 6 H) 0.94-1.18 305 (m, 5 H) I-150

N-hydroxy-3-oxo- 4-(4-(piperidine-1- carbonyl)benzyl)- 3,4-dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide N/A 409 I-151

N-hydroxy-4-(4- methoxybenzyl)-2- methyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.13 (br s, 1 H) 8.99 (br s, 1 H) 7.45 (d, J = 2.05 Hz, 1 H) 7.39 (dd,J = 8.35, 1.91 Hz, 1 H) 7.19 (d, J = 8.79 Hz, 2 H) 7.07 (d, J = 8.21 Hz,1 H) 6.85- 6.93 (m, 2 H) 5.10 (s, 2 H) 4.85-5.02 (m, 1 343 H) 3.71 (s, 3H) 1.51 (d, J = 6.74 Hz, 3 H) I-152

N-hydroxy-2- methyl-4-(4- (methylsulfonyl) benzyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4] oxazine-6- carboxamide ¹H NMR (300 MHz,DMSO-d₆) δ ppm 11.13 (s, 1 H) 8.99 (s, 1 H) 7.90 (d, J = 8.50 Hz, 2 H)7.52 (d, J = 8.50 Hz, 2 H) 7.43 (dd, J = 8.35, 1.91 Hz, 1 H) 7.37 (d, J= 1.76 Hz, 1 H) 7.12 (d, J = 8.21 Hz, 1 H) 5.17- 5.39 (m, 2 H) 4.95-5.06 (m, 1 H) 3.21 (s, 3 H) 1.53 (d, J = 6.74 391 Hz, 3 H) I-153

4-benzyl-N- hydroxy-2-methyl- 3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 11.13 (br s, 1 H)9.00 (br s, 1 H) 7.20-7.43 (m, 7 H) 7.09 (d, J = 8.79 Hz, 1 H) 5.09-5.26 (m, 2 H) 4.92- 5.02 (m, 1 H) 1.52 (d, J = 6.74 Hz, 3 H) 313

Example36—4-benzyl-N-hydroxy-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-154)

Hydroxylamine hydrochloride (14.72 mg, 0.212 mmol),N,N-diisopropylethylamine (0.074 mL, 0.424 mmol) and HATU (48.3 mg,0.127 mmol) were added to a solution of4-benzyl-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid(30 mg, 0.106 mmol) in DMF (2 mL), and the reaction mixture stirred atambient temperature overnight. The reaction was diluted with ethylacetate and washed with brine. The organic layer was separated andconcentrated. The residue was purified with the following conditions:Waters reversed phase HPLC: 23 mL/min, 8 min gradient 35%-85%Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD 5 μm,19×50 mm column. The collected fraction was lyophilized to afford4-benzyl-N-hydroxy-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(6 mg, 19%) as a light pink solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.87(br s, 1H) 8.77 (s, 1H) 7.23-7.35 (m, 5H) 6.90-7.00 (m, 2H) 6.75 (d,J=8.21 Hz, 1H) 4.37-4.63 (m, 2H) 4.02-4.18 (m, 2H) 3.58 (br d, J=6.45Hz, 1H) 1.12 (d, J=6.45 Hz, 3H). MS: (ES, m/z): 299 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 36.

MS Compd. (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-155

N-hydroxy-4-(4- methoxybenzyl)-3- methyl-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.89 (br s, 1 H) 8.78 (s, 1 H) 7.09-7.28 (m, 2 H) 6.82-7.07 (m, 4 H)6.74 (d, J = 8.21 Hz, 1 H) 4.18-4.66 (m, 2 H) 4.08 (d, J = 2.35 Hz, 2 H)3.69-3.76 (m, 3 H) 3.54 (br d, J = 6.45 Hz, 1 H) 1.10 (d, J = 6.74 Hz, 3H) 329

Example 37.(R)-N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-arboxamide(I-162)

Step 1. Synthesis of methyl4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

4-methoxybenzyl chloride (0.135 ml, 0.995 mmol) was added to a solutionof methyl2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (200mg, 0.904 mmol) and cesium carbonate (884 mg, 2.71 mmol) inN,N-Dimethylformamide (5 ml), and the reaction stirred overnight atambient temperature. The reaction was diluted with ethyl acetate andwashed with brine. The organic layer was separated and concentrated thenpurified via column chromatography on a 25 gram silica gel columneluting with 10-50% ethyl acetate-hexane. The desired fractions werecombined and concentrated to afford methyl4-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(275 mg, 89%). MS: (ES, m/z): 342 [M+H]⁺.

Step 2. Synthesis of methyl(R)-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

The racemate of methyl4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(275 mg) was purified by Chiral HPLC with the following conditionsColumn: ChiralPak ID 10*250 mm, 5 μm; Mobile Phase A: Hexanes, MobilePhase B: IPA; Flow rate: 5 mL/min; Gradient: 10% B hold; Runtime: 35minutes, Detector: 220 nm. The first peak was collected and concentratedto give 0.064 g and arbitrarily assigned as methyl(R)-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateMS: (ES, m/z): 342 [M+H]⁺. The second peak was collected andconcentrated to give 0.066 g arbitrarily assigned methyl(S)-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate.MS: (ES, m/z): 342 [M+H]⁺.

Step 3. Synthesis of(R)-N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Intermediate methyl(R)-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(0.030 g, 0.088 mmol, 1.0 equiv) was dissolved in Tetrahydrofuran (0.5mL) and Methanol (0.5 mL). NH₂OH (0.3 ml, 4.54 mmol, 50% in water, 51equiv) and 1N aq. NaOH (0.3 mL, 3.4 equiv) were added. The resultingsolution was stirred for 2 hours at room temperature. The reaction wasconcentrated to dryness. Purified by preparative-HPLC with the followingconditions: Waters reversed phase HPLC: 23 mL/min, 8 min gradient 0%-35%Acetonitrile, 0.1% formic acid on a Waters XBridge Prep C18 OBD 5 am,19×50 mm column. Fractions were lyophilized to afford 0.025 g (90%yield) of(R)-N-hydroxy-4-(4-methoxybenzyl)-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide.MS: (ES, m/z): 343 [M+H]⁺.

Example 38.8-fluoro-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-163)

Step 1: Methyl8-fluoro-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed methyl8-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (100mg, 0.44 mmol, 1.00 equiv), N,N-dimethylformamide (3 mL),1-(chloromethyl)-4-methoxybenzene (0.07 mL, 0.49 mmol, 1.10 equiv),Cs₂CO₃ (362 mg, 1.11 mmol, 2.52 equiv). The resulting solution wasstirred for 2 h at room temperature (25° C.) and then diluted with 15 mLof water, extracted with 2×15 mL of ethyl acetate, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedvia preparative-TLC (eluting with ethyl acetate/petroleum ether (1:3))to afford methyl8-fluoro-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(108 mg, 70%) as a white solid. MS: (ESI, m/z): 346 [M+H]⁺.

Step 2:8-fluoro-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl8-fluoro-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(108 mg, 0.31 mmol, 1.00 equiv), THF/MeOH (4/1) (3 mL), NH₂OH (50% inwater) (1.24 mL, 18.77 mmol, 60.00 equiv). This was followed by theaddition of NaOH (1M) (0.63 mL, 0.63 mmol, 2.00 equiv). The resultingsolution was stirred for 1 h at room temperature (28° C.). The solidswere filtered out. The crude product was purified via Prep-HPLC with thefollowing conditions: Column, XBridge Prep C18 OBD Column, 19×150 mm 5μm; mobile phase, water (0.1% FA) and ACN (15.0% ACN up to 45.0% in 7min); Detector, UV 254 nm. The collected fraction was lyophilized toafford8-fluoro-N-hydroxy-4-(4-methoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(39.3 mg, 36%) as a white solid. ¹H-NMR: (DMSO 300 MHz, ppm): 611.23 (s,1H), 9.11 (s, 1H), 7.38-7.31 (m, 2H), 7.23 (d, J=8.7 Hz, 2H), 6.90 (d,J=8.7 Hz, 2H), 5.13 (s, 2H), 4.95 (s, 2H), 3.72 (s, 3H). MS: (ESI, m/z):347 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 38.

Comp. IUPAC (ESI, m/z) No Structure Name ¹HNMR [M + H]⁺ I-164

4-(4-(1H- pyrazol-1- yl)benzyl)-8- fluoro-N- hydroxy-3- oxo-3,4-dihydro-2H- benzo[b][1,4] oxazine-6- carboxamide (DMSO, 300 MHz, ppm):11.22 (s, 1H), 9.09 (s, 1H), 8.48 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H),7.73 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.39-7.35 (m, 1H), 7.29 (s, 1H),6.54-6.53 (m, 1H), 5.24 (s, 2H), 5.00 (s, 2H) 383

Example 39.N-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxamide(I-165)

Step 1: Methyl1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate

Into a 8-mL vial, was placed methyl2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate (70 mg, 0.34mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), Cs₂CO₃ (275 mg, 0.84mmol, 2.50 equiv), 1-(chloromethyl)-4-methoxybenzene (0.05 mL, 0.37mmol, 1.10 equiv). The resulting solution was stirred for 4 h at roomtemperature (27° C.) and then diluted with 30 mL of water. The resultingsolution was extracted with 3×30 mL of ethyl acetate, washed with 2×30mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with ethyl acetate/petroleum ether (1:4)) to afford methyl1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate(85 mg, 77%) as a white solid. MS: (ESI, m/z): 328 [M+H]⁺.

Step 2:N-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxamide

Into a 8-mL vial, was placed methyl1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxylate(85 mg, 0.26 mmol, 1.00 equiv), THF/MeOH (4:1)(2 mL), NH₂OH (50% inwater) (1.03 mL, 15.59 mmol, 60.00 equiv), NaOH (1M) (0.52 mL, 0.52mmol, 2.00 equiv). The resulting solution was stirred for 2 h at roomtemperature (27° C.). The crude product was purified via Prep-HPLC withthe following conditions: Column, XBridge C18 OBD Prep Column, 100 A, 5μm, 19 mm×250 mm; mobile phase, water (0.1% FA) and ACN (20.0% ACN up to31.0% in 7 min); Detector, UV 254 nm. The collected fraction waslyophilized to affordN-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazine-7-carboxamide(36.2 mg, 42%) as a off-white solid. ¹H-NMR (DMSO, 400 MHz) δ (ppm):11.20 (br, 1H), 9.06 (br, 1H), 7.44-7.42 (m, 1H), 7.34-7.30 (m, 2H),7.23 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.38 (s, 2H), 5.08 (s,2H), 3.71 (s, 3H). MS: (ESI, m/z): 329 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 39.

Comp. IUPAC (ESI, m/z) No. Structure Name ¹HNMR [M + H]⁺ I-166

1-(4-(1H- pyrazol-1- yl)benzyl)-N- hydroxy-2- oxo-1,4- dihydro-2H-benzo[d][1,3] oxazine-7- carboxamide (DMSO, 400 MHz, ppm): 11.20 (br,1H), 9.04 (br, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H),7.72 (s, 1H), 7.46-7.41 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H),6.53-6.52 (m, 1H), 5.43 (s, 2H), 5.18 (s, 2H) 365

Example 40.N-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-167)

Step 1: Methyl4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 8-mL vial, was placed methyl3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (66.5 mg,0.30 mmol, 1.00 equiv), N,N-dimethylformamide (3 mL),1-(chloromethyl)-4-methoxybenzene (0.07 mL, 0.45 mmol, 1.50 equiv),Cs₂CO₃ (195 mg, 0.60 mmol, 2.00 equiv), KI (6 mg, 0.04 mmol, 0.13equiv). The resulting solution was stirred for overnight at 80° C. andthen cooled to room temperature. The resulting solution was diluted with30 mL of water, extracted with 3×30 mL of ethyl acetate, washed with 30mL of brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with ethyl acetate/petroleum ether (1:3)) to afford methyl4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(85 mg, 83%) as yellow oil. MS: (ESI, m/z): 342 [M+H]⁺.

Step 2:N-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 8-mL vial, was placed methyl4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(85 mg, 0.25 mmol, 1.00 equiv), THF/MeOH (4/1)(2 mL), NH₂OH (50% inwater) (0.99 mL, 15.00 mmol, 60.00 equiv), NaOH (1M) (0.5 mL, 0.50 mmol,2.00 equiv). The resulting solution was stirred for overnight at roomtemperature (25° C.). The solids were filtered out. The crude productwas purified by Prep-HPLC with the following conditions: Column, XSelectCSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water (0.1% FA)and ACN (13.0% ACN up to 40.0% in 25 min); Detector, UV 254/220 nm. mLproduct was obtained. The collected fraction was lyophilized to affordN-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(19.8 mg, 23%) as a light brown solid. ¹H-NMR (DMSO, 400 MHz) δ (ppm):10.81 (s, 1H), 8.72 (s, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.92-6.88 (m, 3H),6.74 (d, J=8.4 Hz, 2H), 4.40 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 1.18(s, 6H). MS: (ESI, m/z): 343 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 40.

Comp. IUPAC (ESI, m/z) No. Structure Name ¹HNMR [M + H]⁺ I-168

4-(4-(1H- pyrazol-1- yl)benzyl)-N- hydroxy-3,3- dimethyl-3,4-dihydro-2H- benzo[b][1,4] oxazine-6- carboxamide (DMSO, 400 MHz, ppm):10.84 (s, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H),7.72 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 6.95- 6.92 (m, 1H), 6.78-6.75(m, 2H), 6.52 (s, 1H), 4.51 (s, 2H), 4.05 (s, 2H), 1.21 (s, 6H) 379

Example 41.N6-hydroxy-4-(4-methoxybenzyl)-N2,N2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide(I-169)

Step 1: Methyl2-(dimethylcarbamoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed4-(4-methoxybenzyl)-6-(methoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (50 mg, 0.14 mmol, 1.00 equiv), DMA (2 mL), HATU (62 mg, 0.16 mmol,1.14 equiv), DIEA (65 μL, 0.39 mmol, 2.78 equiv), dimethylaminehydrochloride (13 mg, 0.16 mmol, 1.14 equiv). The resulting solution wasstirred for 1 h at room temperature (25° C.). The resulting solution wasdiluted with 4 mL of water. The solids were collected by filtration anddried to afford methyl2-(dimethylcarbamoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 93%) as yellow oil. MS (ESI, m/z): 385 [M+H]⁺.

Step 2:N⁶-hydroxy-4-(4-methoxybenzyl)-N2,N2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide

Into a 25-mL round-bottom flask, was placed methyl2-(dimethylcarbamoyl)-4-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.13 mmol, 1.00 equiv), THF/MeOH (4/1) (2 mL). This was followedby the addition of NH₂OH (50% in water) (1.19 mL, 19.38 mmol, 120 equiv)and NaOH (1M) (0.3 mL, 0.30 mmol, 2.00 equiv) at 0° C. The resultingsolution was stirred for 3 h at room temperature (25° C.). The mixturewas purified via Prep-HPLC with the following conditions: XBridge ShieldRP18 OBD Column, 5 um, 19×150 mm; Mobile Phase A: Water (0.1% FA),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 55% B in 7min; 254 nm. The collected fraction was lyophilized to affordN6-hydroxy-4-(4-methoxybenzyl)-N2,N2-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,6-dicarboxamide(10.5 mg, 21%) as a pink solid. ¹H-NMR (DMSO, 400 MHz) δ (ppm): 10.95(br, 1H), 8.82 (br, 1H), 7.23-7.18 (m, 3H), 7.01 (d, J=4.4 Hz, 1H), 6.90(d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 1H), 5.13-5.11 (m, 1H), 4.53-4.36(m, 1H), 3.73 (s, 3H), 3.40-3.30 (m, 2H), 3.01 (s, 3H), 2.84 (s, 3H). MS(ESI, m/z): 386 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 41.

Comp. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-170

N⁶-hydroxy-4-(4- methoxybenzyl)-N²- methyl-3,4-dihydro- 2H,benzo[b][1,4]oxazine- 2,6-dicarboxamide (DMSO, 400 MHz, ppm): 10.96 (br,1H), 8.84 (br, 1H), 8.01-8.00 (m, 1H), 7.23-7.19 (m, 3H), 7.06-7.03 (m,1H), 6.90-6.85 (m, 3H), 4.70- 4.67 (m, 1H), 4.42 (s, 2H), 3.73 (s, 3H),3.46- 3.42 (m, 1H), 3.33-3.26 (m, 1H), 2.63 (d, J = 4.8 Hz, 3H) 372I-171

N-hydroxy-4-(4- methoxybenzyl)-2- (morpholine-4- carbonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm):10.95 (br, 1H), 8.83 (br, 1H), 7.23-7.19 (m, 3H), 7.02 (d, J = 8.4 Hz,1H), 6.91 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 5.18-5.16 (m,1H), 4.54-4.35 (m, 2H), 3.73 (s, 3H), 3.54-3.36 (m, 10H) 428 I-172

N6-hydroxy-4-(4- methoxybenzyl)-N2- (tetrahydro-2H- pyran-4-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine- 2,6-dicarboxamide (DMSO, 400 MHz,ppm): 10.96 (br, 1H), 8.83 (br, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.23-7.19(m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.90-6.87 (m, 3H), 4.67-4.65 (m, 1H),4.89-4.37 (m, 2H), 3.83- 3.79 (m, 3H), 3.73 (s, 3H), 3.47-3.43 (m, 1H),3.35-3.25 (m, 3H), 1.66- 1.59 (m, 2H), 1.51-1.44 (m, 2H) 442

Example 42.4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-173)

Step 1: Methyl4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methanol (100 mg, 0.60mmol, 1.00 equiv), tetrahydrofuran (4 mL), methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (124 mg, 0.60mmol, 1.00 equiv), PPh₃ (235 mg, 0.90 mmol, 1.50 equiv), this wasfollowed by the addition of DIAD (0.17 mL, 0.90 mmol, 1.50 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature (25° C.) and then concentrated undervacuum. The residue was purified via preparative TLC (eluting with ethylacetate/petroleum ether (1:1)) to afford methyl4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(160 mg, 75%) as a yellow solid. MS: (ESI, m/z): 357 [M+H]⁺.

Step 2:4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 50-mL round-bottom flask, was placed methyl4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(PH-FMA-PJ94-2113-1) (160 mg, 0.45 mmol, 1.00 equiv), THF/MeOH (4/1) (5mL), NH₂OH (50% in water) (1.80 mL, 26.97 mmol, 60.00 equiv), NaOH (1M)(0.90 mL, 0.90 mmol, 2.00 equiv). The resulting solution was stirred for2 h at room temperature (25° C.). The solids were filtered out. Thecrude product was purified via Prep-HPLC with the following conditions:Column, XBridge Prep C18 OBD Column, 19×150 mm, 5 um; mobile phase,water (10 mmol/L NH₄HCO₃) and ACN (25.0% ACN up to 55.0% in 7 min);Detector, UV 254 nm. The collected fraction was lyophilized to afford4-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(25.7 mg, 16%) as a white solid. ¹H-NMR: (DMSO 300 MHz, ppm): δ 10.60(s, 1H), 8.97 (s, 1H), 7.74 (s, 1H), 7.45-7.43 (m, 1H), 7.41 (d, J=8.1Hz, 1H), 7.18 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 5.10 (s, 2H), 4.85 (s,2H), 4.38-4.35 (m, 2H), 4.23-4.20 (m, 2H). MS: (ESI, m/z): 358 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 42.

Comp. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-174

tert-butyl 2-((6- (hydroxycarbamoyl)- 3-oxo-2,3-dihydro- 4H-benzo[b][1,4]oxazin- 4-yl)methyl)-7,8- dihydro-1,6- naphthyridine-6(5H)-carboxylate (DMSO, 400 MHz, ppm): 11.10 (s, 1H), 8.96 (s, 1H), 7.56-7.54(m, 1H), 7.41-7.38 (m, 2H), 7.09-7.06 (m, 2H), 5.17 (s, 2H), 4.85 (s,2H), 4.50 (s, 2H), 3.66-3.63 (m, 2H), 2.86-2.83 (m, 2H), 1.42 (s, 9H)455 I-175

4-(4-(1H-1,2,4- triazol-1-yl)benzyl)- N-hydroxy-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.12 (br,1H), 9.26 (s, 1H), 8.96 (br, 1H), 8.22 (s, 1H), 7.83 (d, J = 8.4 Hz,2H), 7.50-7.41 (m, 4H), 7.10 (d, J = 9.0 Hz, 1H), 5.26 (s, 2H), 4.91 (s,2H). 366 I-176

N-hydroxy-3-oxo-4- (4-(pyrrolidin-1- yl)benzyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.11 (s, 1H),8.98 (s, 1H), 7.51 (s, 1H), 7.40 7.36 (m, 1H), 7.11-7.02 (m, 3H), 6.48(d, J = 8.7 Hz, 2H), 5.06 (s, 2H), 4.82 (s, 2H), 3.19-3.15 (m, 4H),1.94-1.90 (m, 4H) 368 I-177

N-hydroxy-4-(4- morpholinobenzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.12 (s, 1H),8.99 (s, 1H), 7.48 (s, 1H), 7.41 7.38 (m, 1H), 7.16 (d, J = 8.7 Hz, 2H),7.06 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H), 4.84(s, 2H), 3.72- 3.69 (m, 4H), 3.08- 3.05 (m, 4H) 384 I-178

N-hydroxy-3-oxo-4- ((2-phenyloxazol-5- yl)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm): 11.22 (s, 1H),9.07 (s, 1H), 7.94-7.92 (m, 2H), 7.82 (s, 1H), 7.52-7.45 (m, 4H), 7.29(s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.31 (s, 2H), 4.81 (s, 2H) 366 I-179

N-hydroxy-3-oxo-4- ((2-phenyloxazol-4- yl)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm): 11.17 (s, 1H),9.01 (s, 1H), 8.12 (s, 1H), 7.97-7.94 (m, 2H), 7.70 (s, 1H), 7.53- 7.52(m, 3H), 7.45- 7.42 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H),4.81 (s, 2H) 366 I-180

N-hydroxy-3-oxo-4- ((2-phenyl-2H-1,2,3- triazol-4-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz,ppm): 11.16 (br, 1H), 9.00 (br, 1H), 8.02- 7.96 (m, 3H), 7.69 (s, 1H),7.59-7.53 (m, 2H), 7.45-7.40 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 5.33 (s,2H), 4.84 (s, 2H) 366

Example 43. tert-butyl6-((6-(hydroxycarbamoyl)-3-oxo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(I-181)

Step 1: Methyl4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed tert-butyl6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (83.9 mg,0.32 mmol, 1.20 equiv), DCM (10 mL), TEA (0.06 mL, 0.40 mmol, 1.50equiv). This was followed by the addition of MsCl (0.03 mL, 0.32 mmol,1.2 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 2 h at 0° C. and then concentrated under vacuum to affordtert-butyl6-((methylsulfonyloxy)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylatecrude product. The crude product was then dissolved in 10 mL ofN,N-dimethylformamide, to the above was the added methyl3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazine-6-carboxylate (55 mg, 0.27mmol, 1.00 equiv), Cs₂CO₃ (173 mg, 0.53 mmol, 2.00 equiv). The resultingsolution was stirred for 2 h at room temperature (25° C.) and thendiluted with 30 mL of water, extracted with 2×30 mL of ethyl acetate,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified via preparative-TLC (eluting with ethylacetate/petroleum ether (1:3)) to afford methyl4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(80 mg, 67%) as yellow solid. MS: (ESI, m/z): 453 [M+H]⁺.

Step 2: tert-butyl6-((6-(hydroxycarbamoyl)-3-oxo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate)

Into a 25-mL round-bottom flask, was placed methyl4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(80 mg, 0.18 mmol, 1.00 equiv), THF/MeOH (4/1) (3 mL), NH₂OH (50% inwater) (0.70 mL, 10.62 mmol, 60.00 equiv). This was followed by theaddition of NaOH (1M) (0.35 mL, 0.35 mmol, 2.00 equiv) dropwise withstirring. The resulting solution was stirred for 2 h at room temperature(25° C.). The solids were filtered out. The crude product was purifiedvia Prep-HPLC with the following conditions: Column, XSelect CSH PrepC18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.1% FA) and ACN(25.0% ACN up to 60.0% in 7 min); Detector, UV 254 & 220 nm. Thecollected fraction was lyophilized to afford tert-butyl6-((6-(hydroxycarbamoyl)-3-oxo-2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(29.2 mg, 36.5%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): 611.13(s, 1H), 8.97 (s, 1H), 7.39-7.37 (m, 2H), 7.13-7.05 (m, 4H), 5.13 (s,2H), 4.86 (s, 2H), 4.44 (s, 2H), 3.52-3.49 (m, 2H), 2.73-2.70 (m, 2H),1.41 (s, 9H). MS: (ESI, m/z): 453 [M+H]⁺.

Example 44.N-hydroxy-4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-182)

Step 1: Methyl4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 20-mL vial, was placed methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (83 mg, 0.40 mmol,1.00 equiv), tetrahydrofuran (5 mL), Cs₂CO₃ (264 mg, 0.81 mmol, 2.00equiv), 6-(bromomethyl)-1-methyl-1,2,3,4-tetrahydroquinolinehydrobromide (130 mg, 0.40 mmol, 1.00 equiv). The resulting solution wasstirred for overnight at 60° C. and then cooled to room temperature. Theresulting solution was diluted with 15 mL of water, extracted with 2×15mL of ethyl acetate, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified via preparative TLC(eluting with ethyl acetate/petroleum ether (1:3)) to affordmethyl-4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(15 mg, 10%) as yellow oil. MS: (ESI, m/z): 367 [M+H]⁺.

Step 2:N-hydroxy-4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(15 mg, 0.04 mmol, 1.00 equiv), THF/MeOH (4/1)(1 mL), NH₂OH (50% inwater) (0.16 mL, 2.45 mmol, 60.00 equiv). This was followed by theaddition of NaOH (1M) (0.08 mL, 0.08 mmol, 2.00 equiv) dropwise withstirring. The resulting solution was stirred for 2 h at room temperature(25° C.). The solids were filtered out. The crude product was purifiedvia Prep-HPLC with the following conditions: Column, XBridge Shield RP18OBD Column, 5 μm, 19×150 mm; mobile phase, water (0.1% FA) and ACN (5.0%ACN up to 40.0% in 7 min); Detector, UV 254 nm. The collected fractionwas lyophilized to affordN-hydroxy-4-((1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(2.1 mg, 14%) as a pink solid. ¹H-NMR: (DMSO, 300 MHz, ppm) 611.15 (s,1H), 9.03 (s, 1H), 7.50 (s, 1H), 7.39-7.36 (m, 1H), 7.05-7.02 (m, 1H),6.92-6.90 (m, 1H), 6.84 (s, 1H), 6.50-6.47 (m, 1H), 4.99 (s, 2H), 4.81(s, 2H), 3.14-3.11 (m, 2H), 2.99 (s, 3H), 2.65-2.60 (m, 2H), 1.85-1.84(m, 2H). MS: (ESI, m/z): 368 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 44.

Comp. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-183

N-hydroxy-4-((1- methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)methyl)-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide(DMSO, 400 MHz, ppm): 11.13 (s, 1H), 8.99 (s, 1H), 7.43- 7.38 (m, 2H),7.18- 7.03 (m, 4H), 5.13 (s, 2H), 4.86 (s, 2H), 3.21 (s, 3H), 2.83- 2.80(m, 2H), 2.52- 2.49 (m, 2H) 382 I-184

(+/−)-4-(chroman-2- ylmethyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.20 (s, 1H),9.03 (s, 1H), 7.84- 7.83 (m, 1H), 7.47- 7.44 (m, 1H), 7.08- 7.00 (m,3H), 6.82- 6.77 (m, 1H), 6.67- 6.65 (m, 1H), 4.75 (s, 2H), 4.37-4.24 (m,3H), 2.79-2.70 (m, 2H), 3.07-2.02 (m, 355 1H), 1.78-1.66 (m, 1H) I-185

(+/−)-4-((2,3- dihydrobenzo[b][1,4] dioxin-2-yl)methyl)-N-hydroxy-3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide(DMSO, 300 MHz, ppm): 11.20 (s, 1H), 9.06 (s, 1H), 7.73 (s, 1H),7.47-7.44 (m, 1H, 7.09-7.06 (m, 1H), 6.90-6.78 (m, 4H), 4.80-4.70 (m,2H), 4.56-4.51 (m, 1H), 4.38-4.20 (m, 3H), 4.07-4.01 (m, 1H) 357 I-186

4-(4-acetamidobenzyl)- N-hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.11 (s, 1H),9.93 (s, 1H), 8.97 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 6.9Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9 Hz, 1H), 5.12 (s, 2H),4.86 (s, 2H), 2.01 (s, 3H) 356 I-187

4-(4-(1H-imidazol-1- yl)benzyl)-N-hydroxy- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.13 (br,1H), 8.98 (br, 1H), 8.22 (s, 1H), 7.12 (s, 1H), 7.62 (d, J = 8.7 Hz,2H), 7.44-7.40 (m, 4H), 7.10-7.07 (m, 2H), 5.23 (s, 2H), 4.89 (s, 2H).365 I-188

N-hydroxy-3-oxo-4-(4- (2-oxopyrrolidin-1- yl)benzyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.11 (br,1H), 8.97 (br, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.40- 7.37 (m, 2H), 7.28(d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 1H), 5.16 (s, 2H), 4.87 (s,2H), 3.82-3.77 (m, 2H), 2.46-2.44 (m, 2H), 2.08-2.00 (m, 2H) 382 I-189

4-(4-(N,N- dimethylsulfamoyl) benzyl)-N-hydroxy-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.10 (s, 1H),8.96 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H),7.45-7.41 (m, 1H), 7.34 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H),4.90 (s, 2H), 2.60 (s, 6H) 406 I-190

N-hydroxy-4-(4- (morpholine-4- carbonyl)benzyl)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.12 (s, 1H),8.95 (s, 1H), 7.43- 7.34 (m, 6H), 7.09 (d, J = 8.1 Hz, 1H), 5.22 (s,2H), 4.88 (s, 2H), 3.58-3.43 (m, 8H) 412 I-191

N-hydroxy-3-oxo-4-((5- phenyloxazol-2- yl)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm): 11.15 (s, 1H),9.01 (s, 1H), 7.68- 7.65 (m, 3H), 7.61 (s, 1H), 7.48-7.44 (m, 3H),7.38-7.34 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 4.84 (s, 2H)366 I-192

N-hydroxy-3-oxo-4-(4- (pyrrolidine-1- carbonyl)benzyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 300 MHz, ppm): 11.11 (br,1H), 8.96 (br, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.44- 7.40 (m, 2H), 7.34(d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 5.23 (s, 2H), 4.89 (s,2H), 3.47-3.33 (m, 4H), 1.88-1.77 (m, 4H) 396 I-193

N-hydroxy-3-oxo-4-((1- phenyl-1H-1,2,4- triazol-3-yl)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz,ppm): 11.12 (s, 1H), 9.21 (s, 1H), 8.97 (s, 1H), 7.81-7.79 (m, 1H), 7.66(s, 1H), 7.56-7.52 (m, 2H), 7.43-7.39 (m, 2H), 7.09-7.07 (m, 1H), 5.29(s, 2H), 4.81 (s, 2H) 366 I-213

N-hydroxy-4-((6- methylbenzo[d]oxazol- 2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm):11.11 (s, 1H), 8.99 (s, 1H), 7.60- 7.55 (m, 3H), 7.47 (d, J = 8.4 Hz,1H), 7.18 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 5.46 (s, 2H),4.85 (s, 2H), 2.43 (s, 3H) 354

Example 45.4-(2,4-dimethoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-194)

Step 1: 1-(chloromethyl)-2,4-dimethoxybenzene

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed (2,4-dimethoxyphenyl)methanol(100 mg, 0.59 mmol, 1.00 equiv), dichloromethane (6 mL). This wasfollowed by the addition of thionyl chloride (0.05 mL, 0.71 mmol, 1.20equiv) dropwise with stirring at 0° C. Then a drop of DMF was added tothe mixture. The resulting solution was stirred for 1 h at 0° C. in awater/ice bath. The resulting mixture was concentrated under vacuum toafford 1-(chloromethyl)-2,4-dimethoxybenzene (150 mg, 60% purity) asyellow oil. The product was used to the next step directly withoutfurther purification.

Step 2: Methyl4-(2,4-dimethoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (99 mg, 0.48 mmol,1.00 equiv,). N,N-dimethylformamide (6 mL), Cs₂CO₃ (315 mg, 0.97 mmol,2.00 equiv) and 1-(chloromethyl)-2,4-dimethoxybenzene (150 mg, 0.48mmol, 1.00 equiv, 60% purity). The resulting solution was stirred for 18h at room temperature (16° C.) and then diluted with 20 mL of water,extracted with 3×20 mL of ethyl acetate, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:2)) to afford methyl4-(2,4-dimethoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate)(60 mg, 35%) as an off-white solid. MS: (ESI, m/z): 358 [M+H]⁺.

Step 3:4-(2,4-dimethoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 10-mL round-bottom flask, was placed methyl4-(2,4-dimethoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(60 mg, 0.17 mmol, 1.00 equiv), THF/MeOH (4/1) (4 mL), NH₂OH (50% inwater) (1.3 mL, 20.17 mmol, 120.00 equiv), NaOH (1M) (0.34 mL, 0.34mmol, 2.00 equiv). The resulting solution was stirred for 2 h at roomtemperature (16° C.). The solids were filtered out. The crude productwas purified via Prep-HPLC with the following conditions: Column,XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, water(0.1% FA) and ACN (15.0% ACN up to 55.0% in 7 min); Detector, UV 254 &220 nm. The collected fraction was lyophilized to afford4-(2,4-dimethoxybenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(14.6 mg, 24%) as a white solid. ¹H-NMR (DMSO, 300 MHz) δ (ppm): 11.13(s, 1H), 8.95 (s, 1H), 7.39-7.36 (m, 2H), 7.06 (d, J=8.7 Hz, 1H), 6.86(d, J=8.4 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.43-6.39 (m, 1H), 5.00 (s,2H), 4.84 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H). MS: (ESI, m/z): 359[M+H]⁺.

Example 46.4-(2-(4-fluorophenylamino)-2-oxoethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-195)

Step 1: 2-chloro-N-(4-fluorophenyl)acetamide

Into a 150-mL round-bottom flask, was placed 4-fluoroaniline (2 g, 18.00mmol, 1.00 equiv), DCM (40 mL), TEA (5 mL, 35.97 mmol, 2.00 equiv). Thiswas followed by the addition of 2-chloroacetyl chloride (2.03 mL, 27.00mmol, 1.50 equiv) dropwise with stirring at 0° C. The resulting solutionwas stirred for 5 h at room temperature (20° C.). The resulting mixturewas washed with 1×20 ml of HCl (1 mol/L), 2×20 ml of NaHCO₃ (sat., aq.)and 1×20 mL of brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:10)) to afford2-chloro-N-(4-fluorophenyl)acetamide (2.4 g, 71%) as an off-white solid.MS (ESI, m/z): 188 [M+H]⁺.

Step 2: Methyl4-(2-(4-fluorophenylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (200 mg, 0.97 mmol,1.00 equiv), DMF (3 mL), Cs₂CO₃ (805 mg, 2.47 mmol, 2.55 equiv),2-chloro-N-(4-fluorophenyl)acetamide (273 mg, 1.46 mmol, 1.50 equiv).The resulting solution was stirred for 1 h at room temperature (24° C.).The solids were filtered out. The crude product was purified viareversed phase column with the following conditions: Column, C18 silicagel, 40 g, 20-45 μm, 100 A; Mobile phase: water with 0.5% FA and CH₃CN(10% CH₃CN up to 72% in 30 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford methyl4-(2-(4-fluorophenylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 29%) as a white solid. MS (ESI, m/z): 359 [M+H]⁺.

Step 3:4-(2-(4-fluorophenylamino)-2-oxoethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 50-mL round-bottom flask, was placed methyl4-(2-(4-fluorophenylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(51 mg, 0.14 mmol, 1.00 equiv), THF/MeOH (4/1)(3 mL). Then NaOH (1M)(0.28 mL, 0.28 mmol, 2.00 equiv) and NH₂OH (50% in water) (1.13 mL,17.12 mmol, 122 equiv) were added at 0-10° C. The resulting solution wasstirred overnight at room temperature (27° C.). The crude product waspurified via Prep-HPLC with the following conditions: Column: XSelectCSH Prep C18 OBD Column, 5 um, 19×150 mm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 65% Bin 7 min; 254/220 nm. The collected fraction was lyophilized to afford4-(2-(4-fluorophenylamino)-2-oxoethyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(13.7 mg, 27%) as an off-white solid. ¹H-NMR: (DMSO, 300 MHz, ppm):611.19 (s, 1H), 10.43 (s, 1H), 9.02 (s, 1H), 7.63-7.59 (m, 2H),7.48-7.45 (m, 2H), 7.21-7.09 (m, 3H), 4.80-4.77 (m, 4H). MS (ESI, m/z):360 [M+H]⁺.

Example 47.N-hydroxy-4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-196)

Step 1: (4-(2-methoxyethoxy)phenyl)methanol

Into a 100-mL 3-necked round-bottom flask, was placed4-(hydroxymethyl)phenol (2.49 g, 20.06 mmol, 1.00 equiv), EtOH (20 mL).This was followed by the addition of NaOH (800 mg, 20.00 mmol, 1.00equiv) in water (1 mL). After stirred for 30 min at 80° C.,1-bromo-2-methoxyethane (1.90 mL, 20.00 mmol, 1.00 equiv) was added at80° C. in 20 min. The resulting solution was stirred overnight at 80° C.and then cooled to room temperature, the reaction mixture wasconcentrated under vacuum. The residue was purified via reversed phasecolumn with the following conditions: Column, C18 silica gel, 120 g,20-45 um, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ and CH₃CN(5% CH₃CN up to 60% in 30 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford(4-(2-methoxyethoxy)phenyl)methanol (1.54 g, 42%) as yellow oil. ¹H-NMR:(DMSO, 400 MHz, ppm): δ 7.22 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H),5.06-5.03 (m, 1H), 4.42 (d, J=5.2 Hz, 2H), 4.08-4.06 (m, 2H), 3.66-3.64(m, 2H), 3.31 (s, 3H).

Step 2: Methyl4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed (4-(2-methoxyethoxy)phenyl)methanol(117 mg, 0.64 mmol, 1.00 equiv), THF (20 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (133 mg, 0.64 mmol,1.00 equiv), PPh₃ (253 mg, 0.97 mmol, 1.50 equiv). To this was addedDIAD (0.19 mL, 0.97 mmol, 1.50 equiv) dropwise with stirring under 10°C. The resulting solution was stirred overnight at room temperature (22°C.) and then concentrated under vacuum. The residue was purified viacolumn chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:3)) to afford methyl4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(54 mg, 23%) as yellow oil. MS: (ESI, m/z): 372 [M+H]⁺.

Step 3:N-hydroxy-4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.13 mmol, 1.00 equiv), THF/MeOH (4/1)(2.5 mL). This wasfollowed by the addition of NH₂OH (50% in water) (1.07 mL, 16.19 mmol,125.00 equiv) and NaOH (1M) (0.25 mL, 0.25 mmol, 2.00 equiv) under 10°C. The resulting solution was stirred for 2 h at room temperature (27°C.). The crude product was purified via Prep-HPLC with the followingconditions: Column: XBridge C18 OBD Prep Column, 100 Å, 5 μm, 19 mm×250mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20mL/min; Gradient: 35% B to 55% B in 7 min; 254 nm. The collectedfraction was lyophilized to affordN-hydroxy-4-(4-(2-methoxyethoxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(16.5 mg, 33%) as off-white solid. ¹H-NMR: (DMSO, 300 MHz, ppm): 611.11(br, 1H), 8.99 (s, 1H), 7.45 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.21 (d,J=8.7 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 5.12 (s,2H), 4.86 (s, 2H), 4.07-4.04 (m, 2H), 3.65-3.62 (m, 2H), 3.34 (s, 3H).MS: (ESI, m/z): 373 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 47.

Compd. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-197

N-hydroxy-4-(3-(2- methoxyethoxy)benzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide (DMSO, 300 MHz, ppm): 11.09 (br,1H), 8.99 (s, 1H), 7.41-7.39 (m, 2H), 7.28-7.22 (m, 1H), 7.09-7.07 (m,1H), 6.85-6.84 (m, 3H), 5.15 (s, 2H), 4.88 (s, 2H), 4.08-4.05 (m, 2H),3.65-3.62 (m, 2H), 3.29 (s, 3H) 373

Example 48.N-hydroxy-3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-198)

Step 1: Methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (692 mg, 3.21 mmol, 1.00equiv), THF (50 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (664 mg, 3.21 mmol,1.00 equiv), PPh₃ (1.27 g, 4.84 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.96 mL, 4.84 mmol, 1.50 equiv) dropwise withstirring at 0-10° C. The resulting solution was stirred overnight atroom temperature (23° C.) and then concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:2)) to afford methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(300 mg, 23%) as a white solid. MS (ESI, m/z): 405 [M+H]⁺.

Step 2: Methyl3-oxo-4-(piperidin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(170 mg, 0.42 mmol, 1.00 equiv), DCM (3 mL), TFA (1 mL). The resultingsolution was stirred for 2 h at room temperature (28° C.) and thenconcentrated under vacuum. The residue was purified via reversed phasecolumn with the following conditions: Column, C18 silica gel, 40 g,20-45 μm, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ and CH₃CN(5% CH₃CN up to 55% in 30 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford methyl3-oxo-4-(piperidin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(108 mg, 84%) as a light yellow solid. MS (ESI, m/z): 305 [M+H]⁺.

Step 3: Methyl3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl3-oxo-4-(piperidin-4-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.16 mmol, 1.00 equiv), toluene (10 mL), bromobenzene (52 mg,0.33 mmol, 2.00 equiv), RuPhos (8 mg, 0.02 mmol, 0.10 equiv), 2^(nd)Generation RuPhos precatalyst (26 mg, 0.03 mmol, 0.20 equiv), Cs₂CO₃(161 mg, 0.49 mmol, 3.00 equiv). The resulting solution was stirredovernight at 100° C. and then cooled to room temperature, the solidswere filtered out and the filtrate was concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:2)) to afford methyl3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(35 mg, 56%) as a light yellow solid. MS (ESI, m/z): 381 [M+H]⁺.

Step 4:N-hydroxy-3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 50-mL round-bottom flask, was placed methyl3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(48 mg, 0.13 mmol, 1.00 equiv), THF/MeOH (4/1) (2.5 mL). Then NaOH (1M)(0.25 mL, 0.25 mmol, 2.00 equiv) and NH₂OH (50% in water) (1.00 mL,15.15 mmol, 116.00 equiv) were added 0-10° C. The resulting solution wasstirred for 2 h at room temperature (20° C.). The crude product waspurified via Prep-HPLC with the following conditions: Column: XSelectCSH Prep C18 OBD Column, 5 μm, 19×150 mm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 2% B to 25% Bin 7 min; UV 254/220 nm. The collected fraction was lyophilized toaffordN-hydroxy-3-oxo-4-((1-phenylpiperidin-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(20.9 mg, 43.4%) as an off-white solid. ¹H-NMR: (DMSO, 300 MHz, ppm):611.25 (s, 1H), 9.04 (s, 1H), 7.58 (s, 1H), 7.48-4.45 (m, 1H), 7.20-7.15(m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.1 Hz, 2H), 6.75-6.70 (m,1H), 4.73 (s, 2H), 3.92 (d, J=7.2 Hz, 2H), 3.67-3.65 (m, 2H), 2.63-2.55(m, 2H), 1.92-1.83 (m, 1H), 1.70-1.65 (m, 2H), 1.37-1.34 (m, 2H). MS(ESI, m/z): 382 [M+H]⁺.

Example 49.N-hydroxy-4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-199)

Step 1: 1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one

Into a 250-mL round-bottom flask, was placed piperidin-4-ylmethanol (4g, 34.73 mmol, 1.00 equiv), MeOH (60 mL), DIEA (16.41 mL, 104.34 mmol,3.00 equiv). This was followed by the addition of 2-methylpropanoylchloride (4.3 mL, 41.29 mmol, 1.20 equiv) dropwise with stirring at 0°C., the resulting solution was stirred for 2 h at 0° C. The reaction wasquenched by the addition of 2 mL of water and then concentrated undervacuum. The residue was purified via reversed phase column with thefollowing conditions: Column, C18 silica gel, 120 g, 20-45 μm, 100 A;mobile phase water with 0.5% FA and CH₃CN (5% CH₃CN up to 68% in 30min); Detector, UV 254 nm. The collected fraction was concentrated undervacuum to afford1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one ((1 g, 16%) asa white solid. MS (ESI, m/z): 186 [M+H]⁺.

Step 2: Methyl4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-(4-(hydroxymethyl)piperidin-1-yl)-2-methylpropan-1-one (200 mg, 1.08mmol, 1.00 equiv), THF (72 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (224 mg, 1.08 mmol,1.00 equiv), PPh₃ (262 mg, 1.62 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.32 mL, 1.62 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred overnight at roomtemperature (26° C.) and then concentrated under vacuum. The residue waspurified via reversed phase column with the following conditions:Column, C18 silica gel, 40 g, 20-45 μm, 100 A; Mobile phase: water with0.5% FA and CH₃CN (5% CH3CN up to 50% in 30 min); Detector, UV 254 nm.The collected fraction was concentrated under vacuum to afford methyl4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(45 mg, 11%) as a light yellow solid. MS (ESI, m/z): 375 [M+H]⁺.

Step 3:N-hydroxy-4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 50-mL round-bottom flask, was placed methyl4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(37 mg, 0.10 mmol, 1.00 equiv), THF/MeOH (4/1) (6 mL). Then NaOH (1M)(0.20 mL, 0.20 mmol, 2.00 equiv) and NH₂OH (50% in water) (0.78 mL,11.87 mmol, 119 equiv) were added at 0-10° C. The resulting solution wasstirred for 1 h at room temperature (25° C.). The crude product waspurified via Prep-HPLC with the following conditions: XBridge C18 OBDPrep Column, 100 A, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% FA),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 55% B in 7min; Detector, UV 254 nm. The collected fraction was lyophilized toaffordN-hydroxy-4-((1-isobutyrylpiperidin-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(12.9 mg, 34.7%) as an off-white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): δ11.25 (s, 1H), 9.07 (s, 1H), 7.55 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.08(d, J=8.4 Hz, 1H), 4.72 (s, 2H), 4.38-4.35 (m, 1H), 3.94-3.87 (m, 3H),2.97-2.81 (m, 2H), 2.48-2.40 (m, 1H), 1.89-1.96 (m, 1H), 1.68-1.59 (m,2H), 1.16-0.98 (m, 8H). MS (ESI, m/z): 376 [M+H]⁺.

Example 50.4-((1H-indol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-200)

Step 1: Methyl4-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (134 mg, 0.65 mmol,1.00 equiv), THF (10 mL), Cs₂CO₃ (423 mg, 1.30 mmol, 2.00 equiv). Thentert-butyl 3-(bromomethyl)-1H-indole-1-carboxylate (200 mg, 0.65 mmol,1.00 equiv) was added at 0° C. The resulting solution was stirred for 2h at room temperature (20° C.). The solids were filtered out and thefiltrate was concentrated under vacuum. The residue was purified viareversed phase column with the following conditions: Column, C18 silicagel, 40 g, 20-45 μm, 100 A; Mobile phase: water with 0.5% FA and CH₃CN(5% CH₃CN up to 60% in 30 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford methyl4-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 18%) as a white solid. MS (ESI, m/z): 437 [M+H]⁺.

Step 2: Methyl4-((1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 50-mL round-bottom flask, was placed methyl4-((1-(tert-butoxycarbonyl)-1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.11 mmol, 1.00 equiv), DCM (3 mL), TFA (1 mL). The resultingsolution was stirred for 2 h at room temperature (27° C.) and thenconcentrated under vacuum. The residue was purified via reversed phasecolumn with the following conditions: Column, C18 silica gel, 40 g,20-45 μm, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ and CH₃CN(5% CH₃CN up to 50% in 30 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford methyl4-((1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(20 mg, 52%) as a light yellow solid. MS (ESI, m/z): 337 [M+H]⁺.

Step 3:4-((1H-indol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 50-mL round-bottom flask, was placed methyl4-((1H-indol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(20 mg, 0.06 mmol, 1.00 equiv), THF/MeOH (3 mL). Then NaOH (1M) (0.12mL, 0.12 mmol, 2.00 equiv) and NH₂OH (50% in water) (0.47 mL, 7.14 mmol,119.00 equiv) were added at 0-10° C. The resulting solution was stirredfor 1 h at room temperature (26° C.). The crude product was purified viaPrep-HPLC with the following conditions: XBridge C18 OBD Prep Column,100 A, 5 μm, 19 mm×250 mm; Mobile Phase A: water (0.1% FA), Mobile PhaseB: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 45% B in 7 min; 254 nm.The collected fraction was lyophilized to afford4-((1H-indol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(5.7 mg, 28%) as a pink solid. ¹H-NMR: (DMSO, 400 MHz, ppm): δ 11.15(br, 1H), 11.01 (s, 1H), 9.01 (br, 1H), 7.78 (s, 1H), 7.60 (d, J=7.6 Hz,1H), 7.39-7.32 (m, 3H), 7.08-7.06 (m, 1H), 7.01-6.99 (m, 2H), 5.34 (s,2H), 4.81 (s, 2H). MS (ESI, m/z): 338 [M+H]⁺.

Example 51.4-((1-cyanoindolizin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-201)

Step 1: 2-(chloromethyl)indolizine-1-carbonitrile

Into a 30-mL sealed tube, was placed 1,3-dichloropropan-2-one (3.87 g,30.48 mmol, 1.20 equiv), DMF (10 mL), 2-(pyridin-2-yl)acetonitrile (3 g,25.39 mmol, 1.00 equiv), TMSCl (12.93 mL, 100.30 mmol, 4.00 equiv). Theresulting solution was stirred for 4 h at 100° C. and then cooled toroom temperature, the resulting mixture was concentrated under vacuum,the crude product was purified via reversed phase column with thefollowing conditions: Column, C18 silica gel, 120 g, 20-45 μm, 100 A;mobile phase: water with 0.5% FA and CH₃CN (30% CH₃CN up to 50% in 40min); Detector, UV 254 nm. The collected fraction was concentrated undervacuum to afford 2-(chloromethyl)indolizine-1-carbonitrile (1.1 g, 23%)as a yellow solid. MS: (ESI, m/z): 191 [M+H]⁺.

Step 2: Methyl4-((1-cyanoindolizin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (182 mg, 0.88 mmol,1.00 equiv), DMF (10 mL), 2-(chloromethyl)indolizine-1-carbonitrile)(167 mg, 0.88 mmol, 1.00 equiv), Cs₂CO₃ (572 mg, 1.76 mmol, 2.00 equiv).The resulting solution was stirred for 2.5 h at room temperature (29°C.). The solids were filtered out and the filtrate was concentratedunder vacuum, the crude product was purified via reversed phase columnwith the following conditions: Column, C18 silica gel, 40 g, 20-45 μm,100 A; Mobile phase: water with 0.1% FA and CH₃CN (5% CH₃CN up to 40% in30 min); Detector, UV 254 nm. The collected fraction was concentratedunder vacuum to afford methyl4-((1-cyanoindolizin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 32%) as an off-white solid. MS: (ESI, m/z): 362 [M+H]⁺.

Step 3:4-((1-cyanoindolizin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((1-cyanoindolizin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.14 mmol, 1.00 equiv), THF/MeOH (4/1) (2.5 mL). Then NH₂OH (50%in H₂O) (1.09 mL, 16.5 mmol, 118.00 equiv) and NaOH (1M) (0.3 mL, 0.3mmol, 2.00 equiv) were added at 0-10° C. The resulting solution wasstirred for 2.5 h at room temperature (26° C.). The crude product waspurified via Prep-HPLC with the following conditions: Column: XBridgeC18 OBD Prep Column, 100 A, 5 m, 19 mm×250 mm; Mobile Phase A: water(0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to40% B in 7 min; 254 nm. The collected fraction was lyophilized to afford4-((1-cyanoindolizin-2-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(18.9 mg, 38%) as a light brown solid ¹H-NMR: (DMSO, 400 MHz, ppm):611.11 (br, 1H), 8.97 (br, 1H), 8.44 (d, J=6.8 Hz, 1H), 7.60-7.58 (m,2H), 7.46-7.41 (m, 2H), 7.21-7.17 (m, 1H), 7.10 (d, J=8.4 Hz, 1H),6.91-6.87 (m, 1H), 5.34 (s, 2H), 4.84 (s, 2H). MS: (ESI, m/z): 363[M+H]⁺.

Example 52.N-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-202)

Step 1: 2-(benzyloxy)acetamide

Into a 250-mL round-bottom flask, was placed 7 M NH₃(g)/MeOH (50 mL) andethyl 2-(benzyloxy)acetate (15 g, 77.23 mmol, 1.00 equiv). The resultingsolution was stirred for 5 h at room temperature (25° C.) and thenconcentrated under vacuum. The crude product was recrystallized from 200mL of PE/DCM (20/1) to afford 2-(benzyloxy)acetamide (11 g, 86%) as awhite solid. MS: (ESI, m/z): 166 [M+H]⁺.

Step 2: 2-(benzyloxymethyl)-4-phenyloxazole

Into a 30-mL vial, was placed 2-bromo-1-phenylethan-1-one (4 g, 19.98mmol, 1.00 equiv), DMF (10 mL), 2-(benzyloxy)acetamide (3.3 g, 19.98mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 130° C.and then cooled to room temperature and concentrated under vacuum, theresidue was purified via reversed phase column with the followingconditions: Column, C18 silica gel, 120 g, 20-45 μm, 100 A; Mobilephase: water with 10 mmol/L NH₄HCO₃ and CH₃CN (5% CH₃CN up to 70% in 40min); Detector, UV 254 nm. The collected fraction was concentrated undervacuum to afford 2-(benzyloxymethyl)-4-phenyloxazole (1.1 g, 21%) as ayellow solid. MS: (ESI, m/z): 266 [M+H]⁺.

Step 3: (4-phenyloxazol-2-yl)methanol

Into a 100-mL 3-necked round-bottom flask, was placed2-(benzyloxymethyl)-4-phenyloxazole (900 mg, 3.39 mmol, 1.00 equiv), DCM(20 mL). This was followed by the addition of BBr₃ (1 M) (8.5 mL, 8.5mmol, 2.50 equiv) dropwise with stirring at −78° C. The resultingsolution was stirred for 2 h at room temperature (25° C.) and then thereaction was quenched by the addition of 8 mL of NaHCO₃ (sat., aq.) at0° C. The resulting solution was washed with 3×20 mL of water, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified via column chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:1)) to afford (4-phenyloxazol-2-yl)methanol(320 mg, 54%) as a yellow solid. MS: (ESI, m/z): 176 [M+H]⁺.

Step 4: Methyl3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 30-mL vial, was placed methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (95 mg, 0.46mmol, 1.00 equiv), THF (10 mL), PPh₃ (180 mg, 0.69 mmol, 1.50 equiv),(4-phenyloxazol-2-yl)methanol (80 mg, 0.46 mmol, 1.00 equiv). This wasfollowed by the addition of DIAD (0.13 mL, 0.68 mmol, 1.50 equiv)dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature (25° C.) and then concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with ethyl acetate/petroleum ether (1:2)) to afford methyl3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(200 mg, 96%, 80% purity) as a yellow solid. MS: (ESI, m/z): 365 [M+H]⁺.

Step 5:N-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 30-mL vial, was placed methyl3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 0.22 mmol, 1.00 equiv, 80% purity), THF/MeOH (4/1) (4 mL). ThenNaOH (1M) (0.5 mL, 0.5 mmol, 2.30 equiv) and NH₂OH (50% in water) (2.18mL, 33.00 mmol, 150.00 equiv) were added at 0-10° C. The resultingsolution was stirred for 1 h at room temperature (25° C.). The crudeproduct was purified via Prep-HPLC with the following conditions:Column: XBridge C18 OBD Prep Column, 100 A, 5 μm, 19 mm×250 mm; MobilePhase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min;Gradient: 20% B to 45% B in 7 min; 254 nm. The collected fraction waslyophilized to affordN-hydroxy-3-oxo-4-((4-phenyloxazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(24.8 mg, 27%) as an off-white solid. ¹H-NMR: (DMSO, 300 MHz, ppm): δ11.14 (br, 1H), 9.02 (br, 1H), 8.58 (s, 1H), 7.74-7.69 (m, 3H),7.48-7.29 (m, 4H), 7.11 (d, J=5.4 Hz, 1H), 5.36 (s, 2H), 4.85 (s, 2H).MS: (ESI, m/z): 366 [M+H]⁺.

Example 53.4-((1H-indazol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-203)

Step 1: (1H-indazol-3-yl)methanol

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed 1H-indazole-3-carboxylic acid(5 g, 30.84 mmol, 1.00 equiv), THF (25 mL). This was followed by theaddition of LiAlH₄ (2.30 g, 60.60 mmol, 2.00 equiv) in portions at 0° C.The resulting solution was stirred for 2 h at room temperature (25° C.)and then the reaction was quenched by the addition of 2.3 mL of water,6.9 mL of NaOH (1 M) and 2.3 mL of water at 0° C. The solids werefiltered out. The filtrate was concentrated under vacuum. The residuewas purified via column chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:1)) to afford (1H-indazol-3-yl)methanol (2.0g, 44%) as a white solid. MS (ESI, m/z): 149 [M+H]⁺.

Step 2: tert-butyl 3-(hydroxymethyl)-1H-indazole-1-carboxylate

Into a 25-mL round-bottom flask, was placed (1H-indazol-3-yl)methanol(200 mg, 1.35 mmol, 1.00 equiv), THF (5 mL), TEA (0.21 mL, 1.47 mmol,1.09 equiv), (Boc)₂O (293 mg, 1.34 mmol, 0.99 equiv). The resultingsolution was stirred for overnight at room temperature (25° C.) and thenconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with ethyl acetate/petroleum ether(1:1)) to afford tert-butyl 3-(hydroxymethyl)-1H-indazole-1-carboxylate(130 mg, 39%) as a white solid. MS (ESI, m/z): 249 [M+H]⁺.

Step 3: Methyl4-((1-(tert-butoxycarbonyl)-1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 30-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed tert-butyl3-(hydroxymethyl)-1H-indazole-1-carboxylate (80 mg, 0.32 mmol, 1.00equiv), THF (6 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (66 mg, 0.32 mmol,1.00 equiv), PPh₃ (126 mg, 0.48 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.10 mL, 0.48 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for overnight atroom temperature (25° C.) and then concentrated under vacuum. Theresidue was purified via reversed phase column with the followingconditions: Column, C18 silica gel, 40 g, 20-45 μm, 100 A; Mobile phase:water with 10 mmol/L NH₄HCO₃ and CH₃CN (5% CH₃CN up to 80% in 30 min);Detector, UV 254 nm. The collected fraction was concentrated undervacuum to afford methyl4-((1-(tert-butoxycarbonyl)-1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 71%) as a white solid. MS (ESI, m/z): 438 [M+H]⁺.

Step 4: Methyl4-((1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed methyl4-((1-(tert-butoxycarbonyl)-1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 0.23 mmol, 1.00 equiv), DCM (3 mL), TFA (1 mL). The resultingsolution was stirred for 1.5 h at room temperature (25° C.) and thenconcentrated under vacuum. The residue was purified via reversed phasecolumn with the following conditions: Column, C18 silica gel, 40 g,20-45 μm, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ and CH₃CN(5% CH₃CN up to 70% in 20 min); Detector, UV 254 nm. The collectedfraction was concentrated under vacuum to afford methyl4-((1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 65%) as a white solid. MS (ESI, m/z): 338 [M+H]⁺.

Step 5:4-((1H-indazol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((1H-indazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.15 mmol, 1.00 equiv), THF/MeOH (4/1)(1 mL). This was followedby the addition of NH₂OH (50% in water) (1.17 mL, 17.71 mmol, 119.49equiv) and NaOH (1M) (0.3 mL, 0.3 mmol, 2.00 equiv) at 0-10° C. Theresulting solution was stirred for 3 h at room temperature (25° C.). Themixture was purified via Prep-HPLC with the following conditions:Column, XSelect CSH Prep C18 OBD Column, 100 A, 5 μm, 19×150 mm; Mobilephase A: water (0.1% FA), Mobile phase B: ACN (25.0% B up to 50.0% B in7 min); Detector, UV 254/220 nm. The collected fraction was lyophilizedto afford4-((1H-indazol-3-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(31.7 mg, 63%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): δ 12.98(s, 1H), 11.12 (br, 1H), 8.99 (br, 1H), 7.89 (s, 1H), 7.77 (d, J=8.0 Hz,1H), 7.48 (d, J=8.4 Hz, 1H), 7.36-7.32 (m, 2H), 7.12-7.09 (m, 1H), 7.02(d, J=8.4 Hz, 1H), 5.51 (s, 2H), 4.83 (s, 2H). MS (ESI, m/z): 339[M+H]⁺.

Example 54.N-hydroxy-3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide(I-204)

Step 1: Ethyl5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed ethyl5-phenyl-1H-pyrazole-3-carboxylate (1 g, 4.62 mmol, 1.00 equiv), THF (10mL). This was followed by the addition of NaH (297 mg, 7.43 mmol, 1.61equiv, 60%) in portions at 0° C. The resulting solution was stirred for15 min at room temperature (25° C.). To this was added SEMCl (0.96 mL,5.92 mmol, 1.28 equiv) at 0° C. The resulting solution was stirred for 1h at room temperature (25° C.) and then poured into 10 mL of water/ice.The resulting solution was extracted with 3×15 mL of dichloromethane,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:3)) to afford ethyl5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate)(1.2 g, 75%) as light yellow oil. MS (ESI, m/z): 347 [M+H]⁺.

Step 2:(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methanol

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed ethyl5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole-3-carboxylate(600 mg, 1.73 mmol, 1.00 equiv), THF (5 mL). This was followed by theaddition of LiAlH₄ (132 mg, 3.48 mmol, 2.01 equiv) in portions at 0° C.The resulting solution was stirred for 2 h at room temperature (25° C.)and then the reaction was quenched by the addition of 0.13 mL of water,0.39 mL of NaOH (1 M) and 0.13 mL of water. The solids were filteredout. The filtrate was concentrated under vacuum. The residue waspurified via column chromatography on silica gel (eluting with ethylacetate/petroleum ether (1:1)) to afford(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methanol(400 mg, 76%) as yellow oil. MS (ESI, m/z): 305 [M+H]⁺.

Step 3: Methyl3-oxo-4-[(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Into a 30-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methanol(200 mg, 0.66 mmol, 1.00 equiv), THF (6 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (137 mg, 0.66 mmol,1.00 equiv), PPh₃ (259 mg, 0.99 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.20 mL, 0.98 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for overnight atroom temperature (25° C.) and then concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:3)) to afford methyl3-oxo-4-[(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(300 mg, 93%) as white oil. MS (ESI, m/z): 494 [M+H]⁺.

Step 4: methyl3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed methyl3-oxo-4-[(5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(150 mg, 0.30 mmol, 1.00 equiv), DCM (3 mL), TFA (1 mL). The resultingsolution was stirred for 1 h at room temperature (25° C.) and thenconcentrated under vacuum. The residue was purified via Prep-TLC(eluting with ethyl acetate/petroleum ether (1:3)) to afford methyl3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(100 mg, 92%) as a white solid. MS (ESI, m/z): 364 [M+H]⁺.

Step 5:N-hydroxy-3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(60 mg, 0.17 mmol, 1.00 equiv), THF/MeOH (4/1)(2 mL). Then NH₂OH (50% inwater) (1.31 mL, 19.83 mmol, 120.10 equiv) and NaOH (1M) (0.3 mL, 0.3mmol, 2.00 equiv) were added at 0-10° C. The resulting solution wasstirred for 3 h at room temperature (25° C.). The crude product waspurified via Prep-HPLC with the following conditions: Column, XSelectCSH Prep C18 OBD Column, 100 A, 5 μm, 19×150 mm; Mobile phase A: water(0.1% FA), Mobile phase B: ACN (20.0% B up to 50.0% B in 7 min);Detector, UV 254 nm. The collected fraction was lyophilized to affordN-hydroxy-3-oxo-4-[(5-phenyl-1H-pyrazol-3-yl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide(28.7 mg, 48%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): 613.22(br, 1H), 11.15 (s, 1H), 8.98 (s, 1H), 7.73-7.67 (m, 3H), 7.42-7.32 (m,4H), 7.05 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 5.13 (s, 2H), 4.81 (s, 2H).MS (ESI, m/z): 365 [M+H]⁺.

Example 55.N-hydroxy-3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-205)

Step 1: Ethyl 1-phenyl-1H-imidazole-4-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed ethyl1H-imidazole-4-carboxylate (5 g, 35.68 mmol, 1.00 equiv), DMF (30 mL),iodobenzene (4.80 mL, 42.84 mmol, 1.20 equiv), Cu(OAc)₂ (646 mg, 3.56mmol, 0.10 equiv), Cs₂CO₃ (23.2 g, 71.21 mmol, 2.00 equiv). Theresulting solution was stirred for overnight at 110° C. and then cooledto room temperature, the mixture was poured into 200 mL of water,extracted with 2×60 mL of dichloromethane, washed with 2×40 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:1)) to afford ethyl1-phenyl-1H-imidazole-4-carboxylate (1.5 g, 19%) as a white solid. MS(ESI, m/z): 217 [M+H]⁺.

Step 2: (1-phenyl-1H-imidazol-4-yl)methanol

Into a 25-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed ethyl1-phenyl-1H-imidazole-4-carboxylate (190 mg, 0.88 mmol, 1.00 equiv), THF(10 mL). This was followed by the addition of LiAlH₄ (67 mg, 1.77 mmol,2.01 equiv) in portions at 0° C. The resulting solution was stirred for1 h at room temperature (25° C.) and then the reaction was quenched bythe addition of 0.07 mL of water, 0.20 mL of NaOH (1M) and 0.07 mL ofwater. The solids were filtered out. The filtrate was concentrated undervacuum. The residue was purified via column chromatography on silica gel(eluting with methanol/dichloromethane (1/10)) to afford(1-phenyl-1H-imidazol-4-yl)methanol (120 mg, 78%) as a white solid. MS(ESI, m/z): 175 [M+H]⁺.

Step 3: Methyl3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 30-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed (1-phenyl-1H-imidazol-4-yl)methanol (100 mg, 0.57mmol, 1.00 equiv), THF (5 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (118 mg, 0.57 mmol,1.00 equiv), PPh₃ (225 mg, 0.85 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.17 mL, 0.88 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for overnight atroom temperature (25° C.) and then concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:1)) to afford methyl3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 48%) as a white solid. MS (ESI, m/z): 364 [M+H]⁺.

Step 4:N-hydroxy-3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(60 mg, 0.17 mmol, 1.00 equiv), THF/MeOH (4/1) (2 mL). This was followedby the addition of NH₂OH (50% in water) (1.31 mL, 19.82 mmol, 120.00equiv) and NaOH (1M) (0.3 mL, 0.3 mmol, 2.00 equiv) at 0° C. Theresulting solution was stirred for 3 h at room temperature (25° C.). Thecrude product was purified via Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 100 A, 5 μm, 19×150 mm; Mobilephase A: water (0.1% FA), Mobile phase B: ACN (5.0% B up to 55.0% in 7min); Detector, UV 254 nm. The collected fraction was lyophilized toaffordN-hydroxy-3-oxo-4-((1-phenyl-1H-imidazol-4-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(22.5 mg, 37%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): δ 11.15(s, 1H), 8.98 (s, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.63-7.58 (m, 3H),7.51-7.47 (m, 2H), 7.40-7.32 (m, 2H), 7.05 (d, J=8.4 Hz, 1H), 5.08 (s,2H), 4.79 (s, 2H). MS (ESI, m/z): 365 [M+H]⁺.

Example 56.4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-206)

Step 1: Ethyl 1-cyclopropyl-1H-pyrazole-4-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of O₂, was placed ethyl 1H-pyrazole-4-carboxylate (3 g,21.41 mmol, 1.00 equiv), DCE (50 mL), cyclopropylboronic acid (3.51 g,40.83 mmol, 1.90 equiv), Na₂CO₃ (4.54 g, 40.8 mmol, 1.90 equiv),Cu(OAc)₂ (3.88 g, 21.36 mmol, 1.00 equiv), bipyridine (3.34 g, 21.41mmol, 1.00 equiv). The resulting solution was stirred for overnight at70° C. and then cooled to room temperature. The solids were filteredout. The filtrate was concentrated under vacuum. The residue waspurified via reversed phase column with the following conditions:Column, C18 silica gel, 120 g, 20-45 μm, 100 A; Mobile phase: water with0.5% TFA and CH₃CN (5% CH₃CN up to 80% in 30 min). The collectedfraction was concentrated under vacuum to afford ethyl1-cyclopropyl-1H-pyrazole-4-carboxylate (2.2 g, 57%) as a light yellowsolid. MS (ESI, m/z): 181 [M+H]⁺.

Step 2: (1-cyclopropyl-1H-pyrazol-4-yl)methanol

Into a 50-mL round-bottom flask, was placed ethyl1-cyclopropyl-1H-pyrazole-4-carboxylate (300 mg, 1.66 mmol, 1.00 equiv),THF (10 mL). This was followed by the addition of LiAlH₄ (127 mg, 3.35mmol, 2.01 equiv) in portions at 0° C. The resulting solution wasstirred for 1 h at room temperature (25° C.) and then the reaction wasquenched by the addition of 0.13 mL of water, 0.38 mL of NaOH (1M) and0.13 mL of water. The solids were filtered out, the filtrate wasconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with methanol/dichloromethane(1/10)) to afford (1-cyclopropyl-1H-pyrazol-4-yl)methanol (200 mg, 87%)as a light yellow solid. MS (ESI, m/z): 139 [M+H]⁺.

Step 3: Methyl4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 30-mL vial purged and maintained with an inert atmosphere ofnitrogen, was placed (1-cyclopropyl-1H-pyrazol-4-yl)methanol (100 mg,0.72 mmol, 1.00 equiv), THF (5 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (149 mg, 0.72 mmol,1.00 equiv), PPh₃ (284 mg, 1.08 mmol, 1.50 equiv). This was followed bythe addition of DIAD (0.22 mL, 1.09 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for overnight atroom temperature (25° C.) and then concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:1)) to afford methyl4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(70 mg, 30%) as a light yellow solid. MS (ESI, m/z): 328 [M+H]⁺.

Step 4:4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.15 mmol, 1.00 equiv), THF/MeOH (4/1)(2 mL). This was followedby the addition of NH₂OH (50% in water) (1.21 mL, 18.32 mmol, 120.00equiv) and NaOH (1M) (0.30 mL, 0.30 mmol, 2.00 equiv) at 0° C. Theresulting solution was stirred for 3 h at room temperature (25° C.). Thecrude product was purified via Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 100 A, 5 μm, 19×150 mm; Mobilephase A: water (0.1% FA), Mobile phase B: ACN (35.0% B up to 90.0% in 7min); Detector, UV 254 nm. The collected fraction was lyophilized toafford4-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(23.9 mg, 48%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): 611.19(s, 1H), 9.02 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 7.43-7.37 (m, 2H),7.05 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.76 (s, 2H), 3.68-3.63 (m, 1H),0.98-0.87 (m, 4H). MS (ESI, m/z): 329 [M+H]⁺.

Example 57.N-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-207)

Step 1: N-(2-bromo-5-methylpyridin-3-yl)-2-chloroacetamide

Into a 100-mL round-bottom flask, was placed2-bromo-5-methylpyridin-3-amine (1.00 g, 5.35 mmol, 1.00 equiv),dichloromethane (20 mL), triethylamine (2.24 mL, 16.11 mmol, 3.00equiv). This was followed by the addition of 2-chloroacetyl chloride(0.48 mL, 6.40 mmol, 1.20 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 2 h at 0° C. and then poured into 50mL of water. The mixture was extracted with 3×50 mL of ethyl acetate,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified via column chromatography on silica gel (elutingwith ethyl acetate/petroleum ether (1:3)) to affordN-(2-bromo-5-methylpyridin-3-yl)-2-chloroacetamide (1.20 g, 85%) as anoff-white solid. MS: (ESI, m/z): 263 [M+H]⁺.

Step 2: 2-(chloromethyl)-6-methylthiazolo[5,4-b]pyridine

Into a 20-mL microwave tube, was placedN-(2-bromo-5-methylpyridin-3-yl)-2-chloroacetamide (600 mg, 2.28 mmol,1.00 equiv), toluene (10 mL), P₂S₅ (508 mg, 2.28 mmol, 1.00 equiv). Theresulting solution was stirred for 30 min at 100° C. and then cooled toroom temperature. The resulting mixture was concentrated under vacuum.The residue was diluted with 50 mL of water. The mixture was extractedwith 2×50 mL of dichloromethane, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified via columnchromatography on silica gel (eluting with ethyl acetate/petroleum ether(1:5)) to afford 2-(chloromethyl)-6-methylthiazolo[5,4-b]pyridine (60mg, 13%) as yellow oil. MS: (ESI, m/z): 199 [M+H]⁺.

Step 3: Methyl4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Into a 25-mL round-bottom flask, was placed2-(chloromethyl)-6-methylthiazolo[5,4-b]pyridine (60 mg, 0.30 mmol, 1.00equiv), N,N-dimethylformamide (3 mL), methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (63 mg, 0.30 mmol,1.00 equiv), Cs₂CO₃ (244 mg, 0.75 mmol, 2.50 equiv). The resultingsolution was stirred for 2 h at room temperature (25° C.). The reactionmixture was then poured into 15 mL of water, extracted with 2×15 mL ofethyl acetate, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified via preparative TLC (eluting withethyl acetate/petroleum ether (1:3)) to afford methyl4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(40 mg, 36%) as yellow oil. MS: (ESI, m/z): 370 [M+H]⁺.

Step 4:N-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(40 mg, 0.11 mmol, 1.00 equiv), THF/MeOH (4/1) (2 mL), NH₂OH (50% inwater) (0.43 mL, 6.49 mmol, 60.00 equiv), NaOH (1M) (0.22 mL, 0.22 mmol,2.00 equiv). The resulting solution was stirred for 2 h at roomtemperature (25° C.). The solids were filtered out. The crude productwas purified by Prep-HPLC with the following conditions: Column, XBridgeC18 OBD Prep Column, 100 A, m, 19 mm×250 mm; mobile phase, water (10mmol/L NH4HCO3) and ACN (15.0% ACN up to 35.0% in 7 min); Detector,UV/mass 254 & 220 nm. The collected fraction was lyophilized to affordN-hydroxy-4-((6-methylthiazolo[5,4-b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(6.2 mg, 15%) as a off-white solid. 1H-NMR: (DMSO 300 MHz, ppm): δ 9.00(s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.44 (d, J=8.4 Hz,1H), 7.11 (d, J=8.4 Hz, 1H), 5.60 (s, 2H), 4.87 (s, 2H), 2.43 (s, 3H)MS: (ESI, m/z): 371 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 57.

Comp. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-208

N-hydroxy-4-((6- methoxythiazolo[5,4- b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide (DMSO, 400 MHz,ppm): 11.12 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.60 (s,1H), 7.45 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.61 (s, 2H),4.87 (s, 2H), 3.88 (s, 3H) 387 I-209

4-((6-chlorothiazolo[5,4- b]pyridin-2-yl)methyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide (DMSO, 400 MHz, ppm):11.14 (s, 1H), 9.02 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 7.60 (s, 1H),7.46 (d, J = 8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.65 (s, 2H), 4.89 (s,2H) 391 I-210

N-hydroxy-4-((5- methylthiazolo[5,4- b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide (DMSO, 400 MHz,ppm): 11.11 (s, 1H), 8.99 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.61 (s,1H), 7.45-7.42 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.60 (s, 2H), 4.88 (s,2H), 2.59 (s, 3H) 371 I-211

N-hydroxy-4-((5- methoxythiazolo[5,4- b]pyridin-2-yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-6- carboxamide (DMSO, 400 MHz,ppm): 11.13 (s, 1H), 9.00 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.63 (s,1H), 7.44 (d, J = 8.4 Hz, 1H), (d, J = 8.4 Hz, 1H), 6.97 (d, J = 9.2 Hz,1H), 5.56 (s, 2H), 4.87 (s, 2H), 3.92 (s, 3H) 387 I-212

N-hydroxy-3-oxo-4-((5- (trifluoromethyl)thiazolo[5,4-b]pyridin-2-yl)methyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazine-6-carboxamide (DMSO, 400 MHz, ppm): 11.11 (s, 1H), 9.00 (s, 1H), 8.66 (d,J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J =8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.73 (s, 2H), 4.91 (s, 2H) 425

Example 58:N-hydroxy-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-357)

Step 1: Synthesis of methyl3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

To an oven dried 2 mL reaction vial was added methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (0.2 M in DCE,0.25 mL, 50 μmol), phenylboronic acid (0.2 M in DCE, 0.375 mL, 75 μmol),Et₃N (60 μL) and Cu(OAc)₂ (0.2 M in DMSO, 350 μL, 70 mol). The vial wassealed and shaken at ambient temperature for 3 days. The solvent wasremoved under reduced pressure and to the residue was added EtOAc (500μL) and brine (500 μL). The layers were separated and the aqueous layerwas extracted with EtOAc (500 μL). The combined organic layers wereevaporated to give the crude product as an orange oil, which was used tonext step without further purification. LC_MS: M+1 284.

Step 2. Synthesis ofN-hydroxy-3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

To crude methyl3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (0.2 Min 4:1 THF/MeOH, 250 μL, 50 μmol) was added NH₂OH (50% in water, 120 μL)and NaOH (1 M in water, 100 μL, 100 μmol). The mixture was shaken atambient temperature for 3 hours and the solvent was removed underreduced pressure. The residue was dissolved in a mixture of DMSO (500μL) and HOAc (50 μL) then purified by HPLC to give the titled compoundas light yellow solid (3.2 mg, 22% in 2 steps). LC_MS: M+1 285.

The following compound was prepared according to the procedures forExample 58.

Comp. (ESI, m/z) No. Structure IUPAC Name ¹HNMR [M + H]⁺ I-358

N-hydroxy-4-(3-methoxyphenyl)- 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide 315 0.79

Example 59N-hydroxy-3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-359)

Step-1: methyl3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

2-(chloromethyl)thiazolo[5,4-b]pyridine (178 mg, 0.965 mmol) was addedto a solution of methyl3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (100 mg, 0.483mmol) and cesium carbonate (315 mg, 0.965 mmol) in DMF (2 mL). Thereaction stirred overnight at ambient temperature. The reaction wasdiluted with ethyl acetate (3 mL) and washed with H₂O. The organic phasewas separated and concentrated. The residue was washed with cold MeOHand filtered to afford methyl3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(133.9 mg, 0.377 mmol, 78%) as an off-white solid which was useddirectly in the next step without further purification. MS: (ES, m/z):355 [M+H]⁺.

Step-2:N-hydroxy-3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

methyl3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(133.9 mg, 0.377 mmol) was dissolved in MeOH/THF (1/4) (1 mL) and 50%aqueous hydroxyl amine (0.513 mL, 7.77 mmol). 1N aqueous sodiumhydroxide solution (0.388 mL, 0.388 mmol) was added. The resultingsolution stirred for 6 hours at ambient temperature, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column). The collected fractions werecombined and lyophilized to affordN-hydroxy-3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(3.5 mg, 0.009 mmol, 2.5%) as a white solid. MS: (ES, m/z): 356 [M+H]⁺.

Example 604-(4-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-360)

Step-1: methyl4-(4-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

4-(hydroxymethyl)-N,N-dimethylbenzamide (273 mg, 1.274 mmol),triethylamine (0.168 mL, 1.207 mmol) and methanesulfonyl chloride (0.094mL, 1.207 mmol) were combined in DCM (1 mL) and were stirred at ambienttemperature for 30 minutes. This solution was added to a mixture ofmethyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (264 mg,1.274 mmol) and cesium carbonate (393 mg, 1.207 mmol) in DMF (3 mL) Thereaction stirred at ambient temperature overnight. The reaction wasdiluted with methylene chloride (10 mL) and washed with H₂O (2×5 mL).The organic phases were combined, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified via Biotage (25 g KP-SILcolumn, 15% EtOAc/Hexanes gradient up to 100% EtOAc). The desiredfractions were combined and concentrated to afford methyl4-(4-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(157.7 mg, 0.428 mmol, 35.5%) as an off-white solid. MS: (ES, m/z): 368[M+H]⁺.

Step-2:4-(4-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

methyl4-(4-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(50 mg, 0.136 mmol) was dissolved in MeOH/THF (1/4) (1 mL) and 50%aqueous hydroxyl amine (0.179 mL, 2.71 mmol) and 1N aqueous sodiumhydroxide solution (0.271 mL, 0.271 mmol) were added. The resultingsolution stirred for 4 hours at ambient temperature, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column). The collected fractions werecombined and lyophilized to afford4-(4-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(4.6 mg, 0.012 mmol, 9.2%) as an orange oil. MS: (ES, m/z): 369 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 60.

Compnd. MS (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-361

4-(4- (dimethylamino) benzyl)-N-hydroxy-3- oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO- d₆) δ ppm2.83 (s, 6 H) 4.82 (s, 2 H) 5.05 (s, 2 H) 6.58-6.72 (m, 2 H) 6.97- 7.18(m, 3 H) 7.37 (dd, J = 8.35, 1.91 Hz, 1H) 7.49 (d, J = 1.76 Hz, 1 H)8.26 (s, 1 H). 341

Example 614-(4-carbamoylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-362)

Step-1: methyl4-(4-carbamoylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

4-(bromomethyl)benzamide (273 mg, 1.274 mmol) was added to a solution ofmethyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (264 mg,1.274 mmol) and cesium carbonate (415 mg, 1.274 mmol) in DMF (3 mL), andthe reaction stirred overnight at 50° C. The reaction was diluted withethyl acetate (10 mL) and washed with H₂O (3×3 mL). The organic phaseswere combined, dried over Na₂SO₄, filtered and concentrated to affordmethyl4-(4-carbamoylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(313.8 mg, 0.922 mmol, 72.4%) as a light brown solid which was useddirectly in the next step without further purification. MS: (ES, m/z):340 [M+H]⁺.

Step-2:4-(4-carbamoylbenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

methyl4-(4-carbamoylbenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(313.8 mg, 0.922 mmol) was dissolved in MeOH/THF (1/4) (2.5 mL) and 50%aqueous hydroxyl amine (1.218 mL, 18.44 mmol) and 1N aqueous sodiumhydroxide solution (1.844 mL, 1.844 mmol) were added. The resultingsolution stirred for 2 hours at ambient temperature, and was thenconcentrated to dryness. A portion of the crude product was purified byPrep-HPLC with the following conditions: Waters reversed phase HPLC (23mL/min, 8 min gradient 0%-35% Acetonitrile, 0.1% formic acid on a WatersXBridge Prep C18 OBD 5 μm, 19×50 mm column). The collected fractionswere combined and lyophilized to affordN-hydroxy-3-oxo-4-(thiazolo[5,4-b]pyridin-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamideas a light pink solid. MS: (ES, m/z): 341 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.14-3.19 (m, 1H) 3.54-3.57 (m, 1H) 4.75-5.03 (m, 3H)5.23 (s, 3H) 6.94-7.19 (m, 1H) 7.20-7.51 (m, 6H) 7.69-7.98 (m, 3H) 8.16(s, 1H) 8.98 (br s, 2H) 11.11 (br s, 1H).

The compounds below were synthesized according to the proceduresoutlined above for Example 61.

Compd. MS (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-371

4-(2-fluoro-5- methoxybenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (400 MHz, DMSO-d₆): δ ppm11.14 (s, 1H), 8.99 (s, 1H), 7.45- 7.42 (m, 2H), 7.21- 7.16 (m, 1H),7.10 (d, J = 8 Hz, 1H), 6.89-6.86 (m, 1H), 6.70-6.77 (m, 1H), 5.18 (s,2H), 4.88 (s, 2H), 3.68 (s, 3H) 347

Example 62N-hydroxy-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-363)

Step-1: methyl4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Methyl 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (112 mg,0.540 mmol), imidazo[2,1-b]thiazol-6-ylmethanol (200 mg, 1.298 mmol),triphenylphosphine (0.168 mL, 1.207 mmol) and DIAD (0.094 mL, 1.207mmol) were combined in acetonitrile (1 mL). The reaction was allowed tostir for 16 hours at 50° C. The reaction was diluted with EtOAc (15 mL)and washed with 1N NaOH (5 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated. The crude product was purified via Biotage(25 g KP-SIL column, 12% EtOAc/Hexanes gradient up to 100% EtOAc). Thedesired fractions were combined and concentrated to afford methyl4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(438 mg, 0.510 mmol, 94%; contaminated with triphenylphospine oxide) asa yellow solid. MS: (ES, m/z): 343 [M+H]⁺.

Step-2:N-hydroxy-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(438 mg, 0.510 mmol) was dissolved in MeOH/THF (1/4) (1 mL) and 50%aqueous hydroxyl amine (0.674 mL, 10.21 mmol) and 1N aqueous sodiumhydroxide solution (1.021 mL, 1.021 mmol) were added. The resultingsolution stirred for 16 hours at ambient temperature, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column). The collected fractions werecombined and lyophilized to affordN-hydroxy-4-(imidazo[2,1-b]thiazol-6-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(12.7 mg, 0.037 mmol, 7.2%) as a pale brown solid. MS: (ES, m/z): 344[M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 62.

Compnd. MS (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-364

N-hydroxy-4-((7- methylimidazo[1,2- a]pyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.99- 1.31 (m, 2H) 3.09-3.33 (m, 1H) 4.78 (s, 1H) 4.95- 5.27(m, 2H) 6.98-7.32 (m, 2H) 7.34- 7.52 (m, 1H) 7.53-7.70 (m, 1H) 7.70-7.95 (m, 2H) 8.23 (s, 1H) 341 I-365

N-hydroxy-4-((6- methylimidazo[1,2- a]pyridin-2- yl)methyl)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H) 3.33 (br s, 8H) 4.72- 4.84 (m, 2H) 5.22 (s, 2H)6.95-7.13 (m, 2H) 7.18- 7.53 (m, 2H) 7.57-7.75 (m, 2H) 8.13- 8.30 (m,1H) 352 I-366

4-(3- carbamoylbenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide N/A 342 I-368

4-((6- fluoroimidazo[1,2- a]pyridin-2- yl)methyl)-N- hydroxy-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine- 6-carboxamide N/A 357

Example 63.4-(3-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-367)

Step-1: methyl4-(3-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

Propan-2-amine (0.017 g, 0.302 mmol) was added to a solution of3-((6-(methoxycarbonyl)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)benzoicacid (0.103 g, 0.302 mmol) and triethylamine (0.168 mL, 1.21 mmol) inDCE (1 mL). 2-Chloro-1,3-dimethylimidazolinium chloride (0.076 g, 0.453mmol) was added and the reaction was allowed to stir at ambienttemperature for 1 hour. The reaction was washed with H₂O (2 mL) and theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated to afford methyl4-(3-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylateas an oil. The crude product was used without further purification. MS:(ES, m/z): 383 [M+H]⁺.

Step-2:4-(3-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Methyl4-(3-(dimethylcarbamoyl)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(0.115 g, 0.302 mmol) was dissolved in MeOH/THF (1/4) (1 mL) and 50%aqueous hydroxyl amine (0.399 mL, 6.04 mmol) and 1N aqueous sodiumhydroxide solution (0.604 mL, 0.604 mmol) were added. The resultingsolution stirred for 4 hours at ambient temperature, and was thenconcentrated to dryness. The crude product was purified by Prep-HPLCwith the following conditions: Waters reversed phase HPLC (23 mL/min, 8min gradient 0%-35% Acetonitrile, 0.1% formic acid on a Waters XBridgePrep C18 OBD 5 μm, 19×50 mm column). The collected fractions werecombined and lyophilized to afford4-(3-(dimethylcarbamoyl)benzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(11.0 mg, 0.029 mmol, 9.5%) as a white solid. MS: (ES, m/z): 384 [M+H]⁺.

The compounds below were synthesized according to the proceduresoutlined above for Example 63.

Compnd. MS (ES, m/z) No. Structure IUPAC Name [M + H] I-369

N-hydroxy-4-(4- (isopropylcarbamoyl)benzyl)- 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 384 I-370

N-hydroxy-3-oxo-4-(4- (pyrrolidine-1- carbonyl)benzyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-6- carboxamide 396

Example 64.4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(I-372)

Step 1: 4-(bromomethyl)-3-chlorobenzonitrile

A solution of 3-chloro-4-methylbenzonitrile (1.0 g, 6.60 mmol), NBS (1.4g, 7.87 mmol), and azobisisobutyronitrile (1.08 g, 6.57 mmol) in carbontetrachloride (33 mL) stirred for 4 h at 85° C. The resulting mixturewas cooled to room temperature, washed with 30 mL of water and 30 mL ofbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified via column chromatography onsilica gel (eluting with ethyl acetate/petroleum ether (1:15)) to afford4-(bromomethyl)-3-chlorobenzonitrile (360 mg, 24%) as yellow oil.

Step 2: methyl4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate

A solution of methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(271 mg, 1.31 mmol), 4-(bromomethyl)-3-chlorobenzonitrile (450 mg, 1.86mmol), and cesium carbonate (854 mg, 2.62 mmol) in THF (8 mL) stirredovernight at room temperature. The reaction mixture was filtered, andthe filtrate was concentrated under vacuum. The residue was purified byreversed phase column with the following conditions: Column: C18 column,40 g, 20-45 um, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ andACN (5% ACN up to 70% ACN within 30 min); Detector: UV 254 nm. Thecollected fraction was concentrated under vacuum to afford methyl4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(400 mg, 86%) as a white solid. MS: (ESI, m/z): 357 [M+H]⁺.

Step 3:4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylicacid

A solution of methyl4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate(100 mg, 0.28 mmol) and lithium hydroxide (34 mg, 1.42 mmol) in THF (5mL) and water (2 mL) stirred overnight at room temperature. The pH valueof the reaction mixture was adjusted to 5 with 2 M aqueous HCl solution,and the mixture was extracted with 3×15 mL of ethyl acetate. The organicphase was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by reversed phasecolumn with the following conditions: Column: C18 column, 40 g, 20-45um, 100 A; Mobile phase: water with 10 mmol/L NH₄HCO₃ and ACN (5% ACN upto 40% ACN within 25 min); Detector: UV 254 nm. The collected fractionwas concentrated under vacuum to afford4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylicacid (PH-FMA-PJ94-2283-3) (45 mg, 47%) as a white solid. MS: (ESI, m/z):343 [M+H]⁺.

Step 4:4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

A solution of4-(2-chloro-4-cyanobenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylicacid (40 mg, 0.12 mmol), isopropyl chloroformate (65 uL, 0.59 mmol), and4-methylmorpholine (64 μL, 0.58 mmol) in N,N-dimethyl acetamide (2 mL)stirred for 30 min at room temperature, and then hydroxylaminehydrochloride (40 mg, 0.58 mmol) was added. The resulting solutionstirred overnight at room temperature. The crude product was purified byPrep-HPLC with the following conditions: Column: XBridge Shield RP18 OBDColumn, 5 um, 19×150 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃),Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 15% B to 45% B in 7min; 254 nm. The collected fraction was lyophilized to afford4-(2-chloro-4-cyanobenzyl)-N-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide(10.6 mg, 25%) as a white solid. ¹H-NMR: (DMSO, 400 MHz, ppm): δ 11.13(br, 1H), 8.98 (br, 1H), 8.17 (s, 1H), 7.76 (d, J=8 Hz, 1H), 7.47 (d,J=8.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.17-7.12 (m, 2H), 5.20 (s, 2H),4.91 (s, 2H). MS: (ESI, m/z): 358 [M+H]⁺.

The compound below was synthesized according to the procedures outlinedabove for Example 64.

Compnd. MS (ES, m/z) No. Structure IUPAC Name ¹H NMR [M + H]⁺ I-373

4-(2-chloro-5- cyanobenzyl)-N- hydroxy-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine- 6-carboxamide (DMSO, 400 MHz, ppm): 11.14 (br,1H), 8.98 (br, 1H), 7.84-7.79 (m, 2H), 7.72 (s, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.13 (s, 2H), 5.14 (s, 2H), 4.95 (s, 2H) 358

Example 65—In Vitro Histone Deacetylase Assay

The enzymatic HDAC8 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC8 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates in a total volumeof 25 μL in a reaction buffer composing: 100 mM HEPES, pH7.5, 25 mM KCl,0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (from compounds)2 μM of the fluorescently labeled peptide substrate and enzyme. Theenzyme was added at a final concentration of 1 nM. The peptide substrateRHKK(Ac)—NH2 was used. The compounds were tested at 12 concentrationsspaced by 3× dilution intervals. Negative control samples (0%-inhibitionin the absence of inhibitor) and positive control samples(100%-inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (Pinh) is determinedusing the following equation: Pinh=(PSR0%−PSRinh)/(PSR0%−PSR100%)*100,where PSRinh is the product sum ratio in the presence of inhibitor,PSR0% is the average product sum ration in the absence of inhibitor andPSR100% is the average product sum ratio in 100%-inhibition controlsamples. The IC₅₀ values of inhibitors were determined by fitting the%-inhibition curves with 4 parameter dose-response model using XLfit 4software. Ranges of IC₅₀ values for compounds of the invention aredisclosed in Table 1:

Table 1 provides the compounds arranged according to Inhibition ofproliferation of HDAC8. The compounds are separated into four groups:IC50≤25 nM, IC50>25 nM≤100 nM, IC50>100 nM≤1 μM, IC50>1 μM.

Compounds with HDAC8 IC₅₀ ≤ 25 nM I-9 I-15 I-16 I-17 I-24 I-27 I-35 I-36I-37 I-38 I-62 I-64 I-69 I-70 I-71 I-72 I-73 I-74 I-75 I-77 I-79 I-81I-82 I-88 I-93 I-94 I-99 I-100 I-101 I-103 I-124 I-128 I-132 I-134 I-141I-142 I-143 I-144 I-146 I-147 I-151 I-152 I-160 I-161 I-213 I-217 I-218I-219 I-221 I-222 I-223 I-224 I-242 I-243 I-244 I-245 I-246 I-247 I-248I-251 I-252 I-254 I-256 I-258 I-259 I-263 I-264 I-270 I-272 I-274 I-285I-288 I-290 I-296 Compounds with HDAC8 IC₅₀ > 25 nM ≤ 100 nM I-2 I-4 I-5I-6 I-10 I-11 I-19 I-31 I-32 I-33 I-34 I-44 I-45 I-50 I-53 I-55 I-56I-58 I-59 I-60 I-67 I-68 I-76 I-78 I-84 I-95 I-96 I-98 I-102 I-104 I-105I-118 I-119 I-120 I-121 I-122 I-123 I-127 I-131 I-133 I-135 I-137 I-139I-145 I-149 I-153 I-154 I-155 I-157 I-159 I-162 I-216 I-250 I-253 I-255I-262 I-265 I-267 I-268 I-271 I-273 I-275 I-276 I-278 I-280 I-284 I-286I-292 I-358 Compounds with HDAC8 IC₅₀ > 100 nM ≤ 1 μM I-3 I-7 I-8 I-12I-18 I-20 I-21 I-22 I-23 I-25 I-29 I-30 I-39 I-40 I-41 I-42 I-43 I-46I-48 I-49 I-51 I-52 I-54 I-57 I-61 I-63 I-65 I-66 I-80 I-83 I-85 I-86I-87 I-89 I-90 I-91 I-92 I-106 I-110 I-111 I-112 I-114 I-115 I-116 I-117I-125 I-126 I-129 I-130 I-136 I-138 I-148 I-158 I-249 I-257 I-260 I-269I-277 I-279 I-281 I-282 I-283 I-357 Compounds with HDAC8 IC₅₀ > 1 μM I-1I-13 I-14 I-26 I-28 I-47 I-97 I-107 I-108 I-109 I-113 I-140 I-156

Example 66—HDAC8 Probe Binding Assay

The HDAC8 probe binding assay was performed using a time resolvedfluorescence (TRF) assay format. Recombinant N-terminal GST tagfull-length human HDAC8 was expressed and purified from baculovirus inSf9 insect cells (SignalChem, #H90-30G-1000). Each assay was performedin 1536 black well microplates (Corning, #3936) in a final volume of 4μL in assay buffer containing 50 mM HEPES (pH 7.5), 50 mM KCl, 50 mMNaCl, 0.5 mM GSH (L-Glutathione reduced, Sigma #G4251), 0.03% BGG (0.22μM filtered, Sigma, #G7516-25G), and 0.01% Triton X-100 (Sigma,#T9284-10L). 20 nL of 10-point, 3-fold serial dilution in DMSO waspre-dispensed into respective wells of 1536 assay plates for a finaltest concentration range of 25 μM to 1.3 nM respectively. The finalconcentration in the assay of HDAC8 and probe (a fluorescein labeledpan-HDAC inhibitor) was 2.5 nM and 1.5 nM respectively. 2 μL of 2× probeand 2× anti-GST Terbium (Cisbio, #61GSTXLB) was added to assay platesfollowed by 2 μL of 2×HDAC8. Plates were incubated for 16 hours at roomtemperature before time resolved fluorescence was read on the Envision(Excitation at 340 nm, and Emission at 485 nm and 535 nm, Perkin Elmer).

Data from HDAC8 Assays were reported as percent inhibition (inh)compared with control wells based on the following equation: %inh=1−((FLU−AveLow)/(AveHigh−AveLow)) where FLU=measured time resolvedfluorescence. AveLow=average time resolved fluorescence of no enzymecontrol (n=32). AveHigh=average time resolved fluorescence of DMSOcontrol (n=32). IC₅₀ values were determined by curve fitting of thestandard 4 parameter logistic fitting algorithm included in the ActivityBase software package: IDBS XE Designer Model205. Data is fitted usingthe Levenburg Marquardt algorithm. Ranges of IC₅₀ values for compoundsof the invention are disclosed in Table 2:

Table 2. provides the compounds arranged according to inhibition ofproliferation of HDAC8 determined in a time resolved fluorescence (TRF)assay. The compounds are separated into four groups: IC50≤25 nM, IC50>25nM≤100 nM, IC50>100 nM≤1 μM, IC50≤1 μM.

Compounds Compounds Compounds with HDAC8 with HDAC8 with HDAC8 IC₅₀ ≤ 25nM IC₅₀ ≤ 25 nM IC₅₀ ≤ 25 nM I-33 I-207 I-272 I-36 I-208 I-274 I-37I-209 I-280 I-38 I-210 I-285 I-64 I-211 I-287 I-68 I-213 I-288 I-74I-217 I-289 I-77 I-218 I-290 I-82 I-220 I-291 I-94 I-221 I-294 I-99I-222 I-318 I-100 I-223 I-320 I-101 I-224 I-321 I-102 I-226 I-323 I-103I-227 I-325 I-104 I-231 I-330 I-141 I-232 I-331 I-142 I-233 I-332 I-143I-234 I-333 I-151 I-236 I-334 I-152 I-237 I-335 I-160 I-238 I-336 I-161I-239 I-337 I-165 I-240 I-338 I-166 I-242 I-339 I-175 I-245 I-343 I-176I-246 I-344 I-178 I-247 I-345 I-179 I-248 I-346 I-180 I-251 I-347 I-181I-252 I-348 I-183 I-254 I-350 I-185 I-255 I-351 I-186 I-256 I-352 I-187I-258 I-355 I-189 I-259 I-356 I-191 I-261 I-359 I-196 I-263 I-361 I-197I-264 I-362 I-201 I-266 I-371 I-202 I-270 I-372 I-204 I-340 I-373 I-243I-341 Compounds Compounds Compounds with HDAC8 with HDAC8 with HDAC8IC₅₀ > 25 IC₅₀ > 25 IC₅₀ > 25 nM ≤ 100 nM nM ≤ 100 nM nM ≤ 100 nM I-27I-188 I-295 I-31 I-190 I-296 I-45 I-192 I-298 I-50 I-193 I-299 I-53I-198 I-300 I-54 I-200 I-302 I-58 I-203 I-303 I-59 I-205 I-305 I-60I-206 I-306 I-62 I-212 I-308 I-76 I-215 I-312 I-96 I-216 I-317 I-98I-225 I-319 I-116 I-229 I-322 I-125 I-230 I-324 I-135 I-244 I-327 I-145I-249 I-342 I-147 I-250 I-349 I-149 I-253 I-353 I-150 I-265 I-354 I-154I-267 I-357 I-157 I-268 I-358 I-163 I-271 I-360 I-164 I-273 I-363 I-169I-184 I-292 I-170 I-275 I-364 I-171 I-276 I-365 I-172 I-277 I-368 I-173I-278 I-369 I-177 I-284 I-370 I-182 I-286 Compounds Compounds Compoundswith HDAC8 with HDAC8 with HDAC8 IC₅₀ > 100 IC₅₀ > 100 IC₅₀ > 100 nM ≤ 1μM nM ≤ 1 μM nM ≤ 1 μM I-2 I-167 I-293 I-21 I-168 I-297 I-23 I-174 I-301I-24 I-194 I-304 I-25 I-195 I-307 I-39 I-199 I-310 I-41 I-214 I-311 I-44I-228 I-313 I-46 I-235 I-314 I-57 I-241 I-315 I-66 I-257 I-316 I-93I-260 I-326 I-130 I-262 I-328 I-131 I-269 I-329 I-138 I-279 I-367 I-159I-282 I-162 I-283 Compounds Compounds Compounds with HDAC8 with HDAC8with HDAC8 IC₅₀ > 1 μM IC₅₀ > 1 μM IC₅₀ > 1 μM I-20 I-281 I-309 I-47

EQUIVALENTS

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

The invention claimed is:
 1. A composition comprising a compoundselected from:

or a pharmaceutically acceptable salt thereof.
 2. The composition ofclaim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 3. The composition ofclaim 2, further comprising the compound:

or a pharmaceutically acceptable salt thereof.
 4. The composition ofclaim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 5. The composition ofclaim 4, further comprising the compound:

or a pharmaceutically acceptable salt thereof.
 6. A compositioncomprising a compound selected from:

or a pharmaceutically acceptable salt thereof, wherein the compound isobtained by a process comprising a step of treating a compound:

with hydroxylamine and a first base to form a compound:

wherein R₁ is selected from the group consisting of:


7. The composition of claim 6, wherein the first base comprises ahydroxide ion.
 8. The composition of claim 7, wherein the first base isNaOH.
 9. The composition of claim 6, wherein the process furthercomprises a step of treating a compound:

with R₁—X′, wherein X′ is halogen, and a second base to form thecompound:


10. The composition of claim 9, wherein the second base is NaH, K₂CO₃,or Cs₂CO₃.
 11. The composition of claim 9, wherein X′ is Cl or Br. 12.The composition of claim 6, wherein the composition comprises:

or a pharmaceutically acceptable salt thereof, wherein the compound isobtained by a process, comprising the step of treating the compound:

with hydroxylamine and a first base to form the compound:


13. The composition of claim 12, wherein the process further comprisesthe step of treating the compound:

with R₁—X′, wherein X′ is halogen, and a second base to form thecompound:


14. The composition of claim 6, wherein the composition comprises:

or a pharmaceutically acceptable salt thereof, wherein the compound isobtained by a process, comprising the step of treating the compound:

with hydroxylamine and a first base to form the compound:


15. The composition of claim 14, wherein the process further comprisesthe step of treating the compound:

with R₁—X′, wherein X′ is halogen, and a second base to form thecompound:


16. A composition comprising a first compound selected from:

and a second compound:


17. The composition of claim 16, wherein the first compound is:


18. The composition of claim 16, wherein the first compound is: